2-amino-3-carbonyl imidazopyridine and pyrazolopyridine compounds

ABSTRACT

The present disclosure provides a compound of Formula (I) or pharmaceutically acceptable salt, stereoisomers thereof, a pharmaceutical composition comprising the compound, and a method for treating or preventing an inflammatory and autoimmune diseases, especially neuroinflammation diseases using the compound.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit and priority to U.S. ProvisionalPatent Application No. 63/078,372, filed on 15 Sep. 2020. The entiredisclosure of the application identified in this paragraph isincorporated herein by reference.

FIELD

The present disclosure generally relates to compounds having enzymeinhibitory activity, pharmaceutical compositions comprising thecompound, and methods of using the compounds for treating diseases.

BACKGROUND

Receptor Interacting Protein Kinases (RIPKs) are a family of Ser/Thr andTyr kinases with important roles in inflammation and innate immunity.The kinase activities of RIPK1 and RIPK3 were found to be critical forthe activation of necroptotic cell death pathway by multiple stimuli,including TNFα family of cytokines, interferons (IFNs) and Toll-likereceptor (TLR) ligands (Christofferson and Yuan, 2010; Vanlangenakker etal., 2012). Importantly, RIPK1/3 kinases have been implicated in avariety of pathologic settings that currently lack effective therapies,including stroke, myocardial infarction, retinal injuries, lethalSystemic Inflammatory Response Syndrome (SIRS) and chronic gut and skininflammation, and acute pancreatitis (Linkermann and Green, 2014).

RIPK2 is another RIP kinase involved in the activation of NF-κB,mitogen-activated protein kinases (MAPKs) and apoptosis. The kinaseactivity of RIPK2 is dispensable for signaling via NF-κB and the MAPKJNK (‘Jun N-terminal kinase’) but is required for activation of the MAPKERK2. The best-characterized function of RIPK2 is its mediation ofsignal transduction from the NOD (‘nucleotide-binding oligomerizationdomain’) proteins NOD1 and NOD2, which are cytosolicpathogen-recognition receptors that activate pro-inflammatory andantimicrobial responses in response to bacterial peptidoglycans inmacrophages. NOD1 and NOD2 are homologous proteins composed of caspaserecruitment domains (CARDs), nucleotide-binding domains and leucine-richrepeats. After recognition of its ligands, NOD1 or NOD2 recruits RIPK2via CARD-CARD homotypic interactions. This process promotes theubiquitination of RIPK2 and activation of the TAK1 and IKK complexes,which leads to the activation of NF-κB and MAPKs, as well as theproduction of pro-inflammatory cytokines by macrophages. RIPK2 alsorecruits various ubiquitin E3 ligases to the NOD2 complex, includingXIAP (‘X-chromosome-linked inhibitor of apoptosis’), cIAP1 and cIAP2,PELL3 and LUBAC. It has been demonstrated that XIAP deficiency causesimpaired NOD1- or NOD2-mediated ubiquitination of RIPK2 and inflammatorysignaling. XIAP is recruited to the NOD2-RIPK2 complex via binding tothe kinase domain of RIPK2, which leads to K63-linked ubiquitination ofRIPK2 and recruitment of LUBAC; this results in efficient activation ofNF-κB and MAPKs, as well as cytokine production in macrophages. Theubiquitination sites of RIPK2 (Lys209, Lys410 and Lys538) are essentialfor its function in mediating signaling via NOD1 and NOD2. The D146Nkinase-inactive mutant of RIPK2 retains the ability to bind XIAP and toactivate NOD2 signaling, which suggests that the kinase activity ofRIPK2 is not required for signaling via NOD1 and NOD2.

The NOD2-RIPK2 pathway has attracted special interest due to the role ofthis signaling node in granulomatous inflammatory diseases, includinginflammatory bowel disease (IBD). Such pathologies can arise from eitherpositive or negative dysregulation of the pathway (Caruso et al., 2014;Jostins et al., 2012; Philpott et al., 2014). Genetic variants in NOD2are the strongest susceptibility factor to Crohn's disease (Hugot etal., 2001; Jostins et al., 2012; Ogura et al., 2001a). Crohn'sdisease-associated mutations that abrogate NOD2 binding to MDP mayinduce excessive inflammatory signaling from other pattern recognitionreceptors, including NOD1 (Couturier-Maillard et al., 2013; Inohara etal., 2003). In contrast, mutations in the second major Crohn's diseasesusceptibility factor, ATG16L1, disrupt an inhibitory interaction withNOD2 and consequently increase the activation of RIPK2 (Sorbara et al.,2013). Excessive RIPK2 activation has also been reported in pediatricCrohn's disease (Negroni et al., 2009). In addition, gain of function inthe NOD2-RIPK2 pathway has been linked to Blau syndrome, early-onsetsarcoidosis, allergic airway inflammation, and multiple sclerosis (Gohet al., 2013; Jun et al., 2013; Shaw et al., 2011). Overall, these dataestablish RIPK2 as a key molecule for the understanding of IBDpathogenesis as well as a potential therapeutic target in a widespectrum of inflammatory and autoimmune diseases, includingneuroinflammation diseases.

α-Synuclein is part of a large family of proteins including β- andγ-synuclein and synoretin. α-Synuclein is expressed in the normal stateassociated with synapses and is believed to play a role in neuralplasticity, learning and memory. Several studies have implicatedα-synuclein with a central role in Parkinson disease pathogenesis.Molecular changes in the α-synuclein protein that increase proteinmisfolding and aggregation have a direct role in disease pathogenesis.Aggregation of α-synuclein contributes to the formation of Lewy bodiesand neutrites, the pathologic hallmarks of Parkinson disease andα-synucleinopathies. Activation of tyrosine kinase c-abl contributes toα-synuclein-induced neurodegeneration.

The tyrosine kinase c-abl is tightly regulated non-receptor proteintyrosine kinase involved in a wide range of cellular processes,including growth, survival and stress response (Nat Rev Mol Cell Biol,2004, 5:33-44) and c-abl involved in regulation several cellularprocesses and has implicated in the development of the central nervoussystem by controlling neurogenesis. More recently, increasing evidencefrom various experimental model systems has also revealed that c-abl isactivated in neurodegenerative disease such as Alzheimer's disease,Parkinson's disease, Neiman-Pick type C diseases and tauopathies (HumanMolecular Genetics, 2014, Vol. 23, No. 11).

The stress-signaling non-receptor tyrosine kinase c-abl links parkin tosporadic forms of Parkinson's disease via tyrosine phosphorylation.Tyrosine phosphorylation of parkin by c-abl is a majorpost-translational modification that leads to loss of parkin functionand disease progression in sporadic Parkinson disease. Inhibition ofc-abl offers new therapeutic opportunities for blocking Parkinsondisease progression (The Journal of Neuroscience, 2011, 31(1):157-163).Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative diseasecharacterized by progressive death of motor neurons. Knockdown of c-ablwith small interfering RNAs (siRNAs) also rescued ALS motor neurondegeneration (Imamura et al., Sci. Transl. Med. 9, 2017). MultipleSystem Atrophy (MSA) is a rare, rapidly progressive neurodegenerativedisease without any current treatment. In MSA there is accumulation ofα-synuclein in the neurons and oligodendrocytes of the substantia nigra,striatum, olivopontocerebellar structures and spinal cord (J NeuralTransm Vienna Austria 1996. 2016; 123(6)).

Administration of the tyrosine kinase inhibitor nilotinib decreasesc-abl activity and ameliorates autophagic clearance of α-synuclein intransgenic and lentiviral gene transfer models. Activation of c-abl inthe mouse forebrain induces neurodegeneration in the hippocampus andstriatum. Therefore, an increase in c-abl activity via phosphorylationmay be associated with the α-synuclein pathology detected in Parkinsondisease and other neurodegenerative disease. (Hum Mol Genet. 2013 Aug.15). c-Abl is a potential therapeutic target for α-synucleinopathy,Parkinson disease, Alzheimer disease, ALS, Dementia with Lewy body andMSA.

SUMMARY

The present disclosure provides a compound having RIPK2 and c-abl kinaseinhibitory activity, a composition comprising the compound and a methoduseful to treat an inflammatory and/or autoimmune disease, especiallyneuroinflammation disease. In an embodiment, the compound is a compoundof Formula (I):

In another embodiment, the present disclosure provides pharmaceuticalcompositions comprising a therapeutically effective amount of a compounddescribed herein and a pharmaceutically acceptable carrier.

In yet another embodiment, the present disclosure provides methods ofinhibiting or treating a neurodegenerative disease comprisingadministering to a subject in need thereof a therapeutically effectiveamount of one or more compounds described herein.

DETAILED DESCRIPTION

The following description is merely exemplary in nature and is notintended to limit the present disclosure, application, or uses.

Definitions

The generic terms used in the present disclosure are herein defined forclarity.

This specification uses the terms “substituent”, “radical”, “group”,“moiety”, and “fragment” interchangeably.

As used herein, the term “alkenyl” refers to a straight or branchedhydrocarbonyl group with at least one site of unsaturation, i.e., acarbon-carbon, sp2 double bond. In an embodiment, alkenyl has from 2 to12 carbon atoms. In some embodiments, alkenyl is a C₂-C₁₀ alkenyl groupor a C₂-C₆ alkenyl group. Examples of alkenyl group include, but are notlimited to, ethylene or vinyl (—CH═CH₂), allyl (—CH₂CH═CH₂),cyclopentenyl (—C₅H₇), and 5-hexenyl (—CH₂CH₂CH₂CH₂CH═CH₂).

As used herein, the term “alkoxy” is RO— where R is alkyl. Non-limitingexamples of alkoxy groups include methoxy, ethoxy and propoxy.

As used herein, the term “alkoxyalkyl” refers to an alkyl moietysubstituted with an alkoxy group. Examples of alkoxyalkyl groups includemethoxymethyl, methoxyethyl, methoxypropyl and ethoxyethyl.

As used herein, the term “alkoxycarbonyl” is ROC(O)—, where R is analkyl group as defined herein. In various embodiments, R is a C₁-C₁₀alkyl group or a C₁-C₆ alkyl group.

As used herein, the term “alkyl” refers to a straight or branched chainhydrocarbonyl group. In an embodiment, alkyl has from 1 to 12 carbonatoms. In some embodiments, alkyl is a C₁-C₁₀ alkyl group or a C₁-C₆alkyl group. Examples of alkyl groups include, but are not limited to,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl,hexyl, heptyl, octyl, nonyl and decyl. “Lower alkyl” means alkyl havingfrom 1 to 4 carbon atoms.

As used herein, if the term “C₁-C₆” is used, it means the number ofcarbon atoms is from 1 to 6. For example, C₁-C₆ alkyl means an alkylwhich carbon number is any integer of from 1 to 6.

As used herein, the term “alkylamino” refers to an amino groupsubstituted with one or more alkyl groups. “N-(alkyl)amino” is RNH— and“N,N-(alkyl)₂amino” is R₂N—, where the R groups are alkyl as definedherein and are the same or different. In various embodiments, R is aC₁-C₁₀ alkyl group or a C₁-C₆ alkyl group. Examples of alkylamino groupsinclude methylamino, ethylamino, propylamino, butylamino, dimethylamino,diethylamino, and methylethylamino.

As used herein, the term “alkylaminoalkyl” refers to an alkyl moietysubstituted with an alkylamino group, wherein alkylamino is as definedherein. Examples of alkylaminoakyl groups include methylaminomethyl andethylaminomethyl.

As used herein, the term “alkynyl” refers to a straight or branchedcarbon-chain group with at least one site of unsaturation, i.e., acarbon-carbon, sp triple bond. In an embodiment, alkynyl has from 2 to12 carbon atoms. In some embodiments, alkynyl is a C₂-C₁₀ alkynyl groupor a C₂-C₆ alkynyl group. Examples of alkynyl groups include acetylenic(—C≡CH) and propargyl (—CH₂C≡CH).

As used herein, the term “aryl” refers to any monocyclic or bicycliccarbon ring of up to 7 atoms in each ring, wherein at least one ring isaromatic, or an aromatic ring system of 5 to 14 carbon atoms whichincludes a carbocyclic aromatic group fused with a 5- or 6-memberedcycloalkyl group. Representative examples of aryl groups include, butare not limited to, phenyl, tolyl, xylyl, naphthyl, tetrahydronaphthyl,anthracenyl, fluorenyl, indenyl, azulenyl and indanyl. A carbocyclicaromatic group can be unsubstituted or optionally substituted.

As used herein, the term “cycloalkyl” is a hydrocarbyl group containingat least one saturated or partially unsaturated ring structure, andattached via a ring carbon. In various embodiments, it refers to asaturated or a partially unsaturated C₃-C₁₂ cyclic moiety, examples ofwhich include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl and cyclooctyl. “Cycloalkyloxy” isRO—, where R is cycloalkyl.

As used herein, the terms “halogen” and “halo” refers to chloro (—Cl),bromo (—Br), fluoro (—F) or iodo (—I). “Haloalkoxy” refers to an alkoxygroup substituted with one or more halo groups and examples ofhaloalkoxy groups include, but are not limited to, —OCF₃, —OCHF₂ and—OCH₂F. “Haloalkoxyalkyl” refers to an alkyl moiety substituted with ahaloalkoxy group, wherein haloalkoxy is as defined herein. Examples ofhaloalkoxyalkyl groups include trifluoromethoxymethyl,trifluoroethoxymethyl and trifluoromethoxyethyl. “Haloalkyl” refers toan alkyl moiety substituted with one or more halo groups. Examples ofhaloalkyl groups include —CF₃ and —CHF₂.

As used herein, the term “heteroalkyl” refers to a straight- orbranched-chain alkyl group having from 2 to 14 carbons (in someembodiments, 2 to 10 carbons) in the chain, one or more of which hasbeen replaced by a heteroatom selected from S, O, P and N. Exemplaryheteroalkyls include alkyl ethers, secondary and tertiary alkyl amines,amides, alkyl sulfides, and the like.

As used herein, the term “heterocyclyl” includes the heteroaryls definedbelow and refers to a saturated or partially unsaturated monocyclic,bicyclic or tricyclic group of 2 to 14 ring-carbon atoms and, inaddition to ring-carbon atoms, 1 to 4 heteroatoms selected from P, N, Oand S. In various embodiments, the heterocyclic group is attached toanother moiety through carbon or through a heteroatom, and is optionallysubstituted on carbon or a heteroatom. Examples of heterocyclyl includeazetidinyl, benzoimidazolyl, benzofuranyl, benzofurazanyl,benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl,carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl,indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl,pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl,pyrimidyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroisoquinolinyl,tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, azetidinyl, 1,4-dioxanyl, hexahydroazepinyl, piperazinyl,piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl, thiomorpholinyl,dihydrobenzoimidazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl,dihydrobenzoxazolyl, dihydrofuranyl, dihydroimidazolyl, dihydroindolyl,dihydroisooxazolyl, dihydroisothiazolyl, dihydrooxadiazolyl,dihydrooxazolyl, dihydropyrazinyl, dihydropyrazolyl, dihydropyridinyl,dihydropyrimidinyl, dihydropyrrolyl, dihydroquinolinyl,dihydrotetrazolyl, dihydrothiadiazolyl, dihydrothiazolyl,dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl,methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, andN-oxides thereof. “Heterocyclyloxy” is RO—, where R is heterocyclyl.“Heterocyclylthio” is RS—, where R is heterocyclyl.

As used herein, the term “3- or 4-membered heterocyclyl” refers to amonocyclic ring having 3 or 4 ring atoms wherein at least one ring atomis heteroatom selected from the group consisting of N, O and S.Non-limiting examples of 3- or 4-membered heterocyclyl includeaziridinyl, 2H-azirinyl, oxiranyl, thiiranyl, azetidinyl,2,3-dihyroazetyl, azetyl, 1,3-diazetidinyl, oxetanyl, 2H-oxetyl,thietanyl, and 2H-thietyl.

As used herein, the term “heteroaryl” refers to a monocyclic, bicyclicor tricyclic ring having up to 7 atoms in each ring, wherein at leastone ring is aromatic and contains from 1 to 4 heteroatoms in the ringselected from the group consisting of N, O and S. Non-limiting examplesof heteroaryl include pyridyl, thienyl, furanyl, pyrimidyl, imidazolyl,pyranyl, pyrazolyl, thiazolyl, thiadiazolyl, isothiazolyl, oxazolyl,isoxazoyl, pyrrolyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl,benzofuranyl, dibenzofuranyl, dibenzothiophenyl, benzothienyl, indolyl,benzothiazolyl, benzooxazolyl, benzimidazolyl, isoindolyl,benzotriazolyl, purinyl, thianaphthenyl and pyrazinyl. Attachment ofheteroaryl can occur via an aromatic ring, or, if heteroaryl is bicyclicor tricyclic and one of the rings is not aromatic or contains noheteroatoms, through a non-aromatic ring or a ring containing noheteroatoms. “Heteroaryl” is also understood to include the N-oxidederivative of any nitrogen containing heteroaryl. “Heteroaryloxy” isRO—, where R is heteroaryl.

As used herein, the term “hydroxyalkoxy” refers to an alkoxy groupsubstituted with a hydroxyl group (—OH), wherein alkoxy is as definedherein. An example of hydroxyalkoxy is hydroxyethoxy.

As used herein, the term “hydroxyalkyl” refers to a linear or branchedmonovalent C₁-C₁₀ hydrocarbon group substituted with at least onehydroxy group and examples of hydroxyalkyl groups include, but are notlimited to, hydroxymethyl, hydroxyethyl, hydroxypropyl and hydroxybutyl.

As used herein, the term “pharmaceutically acceptable” means suitablefor use in pharmaceutical preparations, generally considered as safe forsuch use, officially approved by a regulatory agency of a national orstate government for such use, or being listed in the U.S. Pharmacopoeiaor other generally recognized pharmacopoeia for use in animals, and moreparticularly in humans.

As used herein, the term “pharmaceutically acceptable carrier” refers toa diluent, adjuvant, excipient, or carrier, or other ingredient which ispharmaceutically acceptable and with which a compound of the inventionis administered.

As used herein, the term “pharmaceutically acceptable salt” refers to asalt which may enhance desired pharmacological activity. Examples ofpharmaceutically acceptable salts include acid addition salts formedwith inorganic or organic acids, metal salts and amine salts. Examplesof acid addition salts formed with inorganic acids include salts withhydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid andphosphoric acid. Examples of acid addition salts formed with organicacids such as acetic acid, propionic acid, hexanoic acid, heptanoicacid, cyclopentane-propionic acid, glycolic acid, pyruvic acid, lacticacid, malonic acid, succinic acid, malic acid, maleic acid, fumaricacid, tartaric acid, citric acid, benzoic acid,o-(4-hydroxy-benzoyl)-benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid,2-hydroxyethane-sulfonic acid, benzenesulfonic acid,p-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,p-toluenesulfonic acid, camphorsulfonic acid,4-methyl-bicyclo[2.2.2]oct-2-ene1-carboxylic acid, gluco-heptonic acid,4,4′-methylenebis(3-hydroxy-2-naphthoic) acid, 3-phenylpropionic acid,trimethyl-acetic acid, tertiary butylacetic acid, lauryl sulfuric acid,gluconic acid, glutamic acid, hydroxy-naphthoic acids, salicylic acid,stearic acid and muconic acid. Examples of metal salts include saltswith sodium, potassium, calcium, magnesium, aluminum, iron, and zincions. Examples of amine salts include salts with ammonia and organicnitrogenous bases strong enough to form salts with carboxylic acids.

As used herein, the term “substituted” means any of above groups (i.e.,alkyl, aryl, heteroaryl, heterocycle or cycloalkyl) wherein at least onehydrogen atom of the moiety being substituted is replaced with asubstituent. In one embodiment, each carbon atom of the group beingsubstituted is substituted with no more than two substituents. Inanother embodiment, each carbon atom of the group being substituted issubstituted with no more than one substituent. In the case of a ketosubstituent, two hydrogen atoms are replaced with an oxygen which isattached to the carbon via a double bond. Unless specifically defined,substituents include halogen, hydroxyl, (lower) alkyl, haloalkyl, mono-or di-alkylamino, aryl, heterocycle, —NO₂, B(OH)₂, BPin, —NR_(a)R_(b),—NR_(a)C(═O)R_(b), —NR_(a)C(═O)NR_(a)R_(b), —NR_(a)C(═O)OR_(b),—NR_(a)SO₂R_(b), —OR_(a), —CN, —C(═O)R_(a), —C(═O)OR_(a),—C(═O)NR_(a)R_(b), —OC(═O)R_(a), —OC(═O)OR_(a), —OC(═O)NR_(a)R_(b),—NR_(a)SO₂R_(b), —PO₃R_(a), —PO(OR_(a))(OR_(b)), —SO₂R_(a), —S(O)R_(a),—SO(N)R_(a) (e.g., sulfoximine), —(R_(a))S═NR_(b) (e.g., sulfilimine)and —SR_(a), wherein R_(a) and R_(b) are the same or different andindependently hydrogen, halogen, amino, alkyl, haloalkyl, aryl orheterocycle, or wherein R_(a) and R_(b) taken together with the nitrogenatom to which they are attached form a heterocycle. R_(a) and R_(b) maybe in the plural based on atoms which those are attached to.

As used herein, the term “therapeutically effective amount” means whenapplied to a compound of the invention is intended to denote an amountof the compound that is sufficient to ameliorate, palliate, stabilize,reverse, slow or delay the progression of a disorder or disease state,or of a symptom of the disorder or disease. In an embodiment, the methodof the present invention provides for administration of combinations ofcompounds. In such instances, the “therapeutically effective amount” isthe amount of a compound of the present invention in the combinationsufficient to cause the intended biological effect.

As used herein, the term “treatment” or “treating” as used herein meansameliorating or reversing the progress or severity of a disease ordisorder, or ameliorating or reversing one or more symptoms or sideeffects of such disease or disorder. “Treatment” or “treating”, as usedherein, also means to inhibit or block, as in retard, arrest, restrain,impede or obstruct, the progress of a system, condition or state of adisease or disorder. For purposes of this invention, “treatment” or“treating” further means an approach for obtaining beneficial or desiredclinical results, where “beneficial or desired clinical results”include, without limitation, alleviation of a symptom, diminishment ofthe extent of a disorder or disease, stabilized (i.e., not worsening)disease or disorder state, delay or slowing of a disease or disorderstate, amelioration or palliation of a disease or disorder state, andremission of a disease or disorder, whether partial or total.

In another embodiment, the compounds of Formula (I) are used formodulating the activity of a RIPK2 protein.

As used herein, the term “modulating” or “modulation” refers to thealteration of the catalytic activity of a protein kinase. In particular,modulating refers to the activation or inhibition of the catalyticactivity of a protein kinase, depending on the concentration of thecompound or salt to which the protein kinase is exposed or, morepreferably, the inhibition of the catalytic activity of a proteinkinase. The term “catalytic activity” as used herein refers to the rateof phosphorylation of tyrosine, serine or threonine under the influence,direct or indirect, of a protein kinase.

The three main classes that pharmacological inhibitors of kinaseactivity are categorized by are (1) Type I, or “DFG-in” ATP competitiveinhibitors, which directly compete with ATP in the ATP binding site(i.e., dual SRC ABL inhibitor dasatinib, (2) Type II, or “DFG-out” ATPcompetitive inhibitors, which, in addition to binding the ATP bindingsite also engage an adjacent hydrophobic binding site that is onlyaccessible when the kinase is in an inactivated configuration (i.e., theactivation loop is oriented in a conformation that would block substratebinding) (i.e., imatinib, nilotinib), and (3) non-ATP competitiveinhibitors that bind at sites outside the ATP binding site that affectthe activity of the kinase (i.e. GNF-2).

As used herein, the phrase “compound(s) of this/the disclosure” includesany compound(s) of Formula (I), as well as clathrates, hydrates,solvates, or polymorphs thereof. And, even if the term “compound(s) ofthe disclosure” does not mention its pharmaceutically acceptable sat,the term includes salts thereof. In one embodiment, the compounds ofthis disclosure include stereochemically pure compounds, e.g., thosesubstantially free (e.g., greater than 85% ee, greater than 90% ee,greater than 95% ee, greater than 97% ee, or greater than 99% ee) ofother stereoisomers. That is, if the compounds of Formula (I) accordingto the present disclosure or salts thereof are tautomeric isomers and/orstereoisomers (e.g., geometrical isomers and conformational isomers),such isolated isomers and their mixtures also are included in the scopeof this disclosure. If the compounds of the present disclosure or saltsthereof have an asymmetric carbon in their structures, their activeoptical isomers and their racemic mixtures also are included in thescope of this disclosure.

As used herein, the term “polymorph” refers to solid crystalline formsof a compound of this disclosure or complex thereof. Differentpolymorphs of the same compound can exhibit different physical, chemicaland/or spectroscopic properties. Different physical properties include,but are not limited to stability (e.g., to heat or light),compressibility and density (important in formulation and productmanufacturing), and dissolution rates (which can affectbioavailability). Differences in stability can result from changes inchemical reactivity (e.g., differential oxidation, such that a dosageform discolors more rapidly when comprised of one polymorph than whencomprised of another polymorph) or mechanical characteristics (e.g.,tablets crumble on storage as a kinetically favored polymorph convertsto thermodynamically more stable polymorph) or both (e.g., tablets ofone polymorph are more susceptible to breakdown at high humidity).Different physical properties of polymorphs can affect their processing.For example, one polymorph might be more likely to form solvates ormight be more difficult to filter or wash free of impurities thananother due to, for example, the shape or size distribution of particlesof it.

As used herein, the term “solvate” means a compound or its saltaccording to this disclosure that further includes a stoichiometric ornon-stoichiometric amount of a solvent bound by non-covalentintermolecular forces. Preferred solvents are volatile, non-toxic,and/or acceptable for administration to humans in trace amounts.

As used herein, the term “hydrate” means a compound or its saltaccording to this disclosure that further includes a stoichiometric ornon-stoichiometric amount of water bound by non-covalent intermolecularforces.

As used herein, the term “clathrate” means a compound or its salt in theform of a crystal lattice that contains spaces (e.g., channels) thathave a guest molecule (e.g., a solvent or water) trapped within.

Compounds of the Present Disclosure

The present disclosure provides a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

R¹ and R² are independently —H, C₁-C₆ alkyl, C₃-C₆ carbocyclyl, C₁-C₄alkanoyl (i.e., —(CO)C₁-C₄ alkyl), —(CO)C₃-C₆ carbocyclyl, aryl, orheteroaryl, wherein each carbon is optionally substituted with one ormore groups selected from the group consisting of halo, alkyl,hydroxyalkyl, haloalkyl, and monoalkylaminoalkyl; or R¹ and R² togetherform a 5-member heterocycle;

R³ is —H, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl,—O-cycloalkyl, —O-heterocyclyl, —O-aryl, —O-heteroaryl, —NR_(c)-alkyl,—NR_(c)-cycloalkyl, —NR_(c)-heterocyclyl, —NR_(c)-aryl,—NR_(c)-heteroaryl, —NR_(c)—NR_(c) C(═O)R_(c) or —CF₃, wherein eachcarbon is optionally substituted with one or more groups selected fromthe group consisting of halo, alkyl, hydroxyalkyl, haloalkyl, andmonoalkylaminoalkyl;

R⁴ and R⁵ are independently —H, —OH, halo, C₁-C₆ alkyl, C₁-C₆ alkoxy,aryl, heteroaryl, heterocyclyl, or heteroalkyl, amino, —SCH₃, or —CN;

R⁶ is selected from the group consisting of —H, halo, C₁-C₆ alkyl, C₁-C₆alkoxy, C₃-C₆ carbocyclyl, heterocyclyl, aryl, heteroaryl, —NR_(c)-aryl,—NR_(c)-heteroaryl, —O-aryl, —O-heteroaryl, wherein R⁶ is optionallysubstituted with one or more groups selected from the group consistingof halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl,aminoalkyl, trimethylsilylethoxymethyl, morpholinyl, piperazinyl,methylpiperazinyl, alkoxyalkenyl, —NO₂, —NR_(a)R_(b), —NR_(a)C(═O)R_(b),—NR_(a)C(═O)NR_(a)R_(b), —NR_(a)C(═O)OR_(b), —OR_(a), —SR_(a), —CN,—C(═O)R_(a), —C(═O)OR_(a), —C(═O)NR_(a)R_(b), —OC(═O)R_(a),—OC(═O)OR_(a), and —OC(═O)NR_(a)R_(b);

R_(a) and R_(b) are independently —H, halo, amino, alkyl, or haloalkyl;

R_(c) is —H, C₁-C₃ alkyl, or cyclopropyl; and

X and Y are independently carbon or nitrogen, wherein X is N when Y isC, or X is C when Y is N.

In some embodiments, R³ is selected from the group consisting of —H,methyl, isopropyl, butyl, methoxy, pyridinyl, phenyl, cyclopropyl,cyclobutyl, pyrazolyl, azetidinyl, pyrimidinyl, pyrrolidinyl,cyclopropylamino, and indazolyl, wherein R³ is optionally substitutedwith one or more groups selected from the group consisting of halo,alkyl, hydroxyalkyl, haloalkyl, and monoalkylaminoalkyl. Non-limiting,representative compounds having such substitutions can be found in Table1.

In some embodiments, R⁶ is selected from the group consisting of bromo,phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, aza-indolinyl,indolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl,thiophenyl, furanyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl,pyrrolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl,imidazolopyridinyl, imidazolopyridinyl, imidazolopyrimidinyl,imidazopyrazinyl, pyrrolotriazinyl, pyrazolopyridinyl,imidazolotriazinyl, purinyl, indazolyl, benzofuranyl, benzothiophenyl,benzooxazolinyl, benzothiazolinyl, benzoimidazolyl, oxoindolinyl,quinolinyl, aza-quinolinyl, isoquinolinyl, aza-isoquinolinyl,quinazolinyl, aza-quinazolinyl, quinoxalinyl, aza-quinoxalinyl,naphthalenyl, wherein R⁶ is optionally substituted with one or moregroups selected from the group consisting of halo, hydroxyl, alkyl,alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl, aminoalkyl,alkylamino, trimethylsilylethoxymethyl, morpholinyl, piperazinyl,methylpiperazinyl, and alkoxyalkenyl. Non-limiting, representativecompounds having such substitutions can be found in Table 1.

In one embodiment, the compound of Formula (I) is selected fromcompounds according to Formula (II) and pharmaceutically acceptablesalts thereof:

wherein R³, R⁴, R⁵ and R⁶ are as defined above.

In some embodiments, R³ is fluorocyclopropyl and R⁶ is indolyl which isoptionally substituted with one or more groups selected from the groupconsisting of halo, hydroxyl, alkyl, haloalkyl, hydroxyalkyl,aminoalkyl, and tert-butoxycarbonyl. Non-limiting, representativecompounds having such substitutions can be found in Table 1.

In some embodiments, R³ is fluorocyclopropyl, and R⁶ is selected fromthe group consisting of bromo, phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, aza-indolinyl, indolyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, oxazolyl,thiazolyl, oxadiazolyl, thiadiazolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazolopyridinyl,imidazolopyridinyl, imidazolopyrimidinyl, imidazopyrazinyl,pyrrolotriazinyl, pyrazolopyridinyl, imidazolotriazinyl, purinyl,indazolyl, benzofuranyl, benzothiophenyl, benzooxazolinyl,benzothiazolinyl, benzoimidazolyl, oxoindolinyl, quinolinyl,aza-quinolinyl, isoquinolinyl, aza-isoquinolinyl, quinazolinyl,aza-quinazolinyl, quinoxalinyl, aza-quinoxalinyl, naphthalenyl, whereinR⁶ is optionally substituted with one or more groups selected from thegroup consisting of halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,haloalkoxy, hydroxyalkyl, aminoalkyl, alkylamino,trimethylsilylethoxymethyl, morpholinyl, piperazinyl, methylpiperazinyl,and alkoxyalkenyl. Non-limiting, representative compounds having suchsubstitutions can be found in Table 1.

In some embodiments, R³ is cyclopropyl and R⁶ is selected from the groupconsisting of bromo, phenyl, pyridinyl, pyrimidinyl, pyridazinyl,pyrazinyl, aza-indolinyl, indolyl, pyrrolyl, pyrazolyl, imidazolyl,triazolyl, tetrazolyl, thiophenyl, furanyl, oxazolyl, thiazolyl,oxadiazolyl, thiadiazolyl, pyrrolopyridinyl, pyrrolopyrimidinyl,pyrazolopyrimidinyl, imidazolopyridinyl, imidazolopyridinyl,imidazolopyrimidinyl, imidazopyrazinyl, pyrrolotriazinyl,pyrazolopyridinyl, imidazolotriazinyl, purinyl, indazolyl, benzofuranyl,benzothiophenyl, benzooxazolinyl, benzothiazolinyl, benzoimidazolyl,oxoindolinyl, quinolinyl, aza-quinolinyl, isoquinolinyl,aza-isoquinolinyl, quinazolinyl, aza-quinazolinyl, quinoxalinyl,aza-quinoxalinyl, naphthalenyl, wherein R⁶ is optionally substitutedwith one or more groups selected from the group consisting of halo,hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl, haloalkoxy, hydroxyalkyl,aminoalkyl, alkylamino, trimethylsilylethoxymethyl, morpholinyl,piperazinyl, methylpiperazinyl, and alkoxyalkenyl. Non-limiting,representative compounds having such substitutions can be found in Table1.

In some embodiments, R³ is selected from the group consisting of methyl,isopropyl, butyl, methoxy, pyridinyl, phenyl, cyclobutyl, pyrazolyl,azetidinyl, pyrimidinyl, pyrrolidinyl, cyclopropylamino, and indazolyl,wherein R³ is optionally substituted with one or more groups selectedfrom the group consisting of halo, alkyl, hydroxyalkyl, haloalkyl, andmonoalkylaminoalkyl. Non-limiting, representative compounds having suchsubstitutions can be found in Table 1.

In another embodiment, the compound of Formula (I) is selected fromcompounds according to Formula (III) and pharmaceutically acceptablesalts thereof:

wherein R³, R⁴, R⁵ and R⁶ are as defined above. Non-limiting,representative compounds having such substitutions can be found in Table1.

In some embodiments, the compounds of Formula I have R¹ and R² which areindependently —H, alkyl, acetyl, tert-butoxycarbonyl, aminoethyl,dimethylaminoethyl, or methylaminoethyl; or R¹ and R² together forming a5-member heterocyclic group. Non-limiting, representative compoundshaving such substitutions can be found in Table 1, wherein R³ to R⁶ areas defined above for Formula (I).

The present disclosure provides pharmaceutically acceptable salts of thecompounds described above. The pharmaceutically acceptable salts are asdefined above in the definition section. In some embodiments, the saltis hydrochloric acid salt, tartaric acid salt, phosphoric acid salt, ormaleic acid salt.

Medical Uses and Methods of Treatment Using the Compounds According tothe Present Disclosure

The present disclosure further provides methods for treating aneurodegenerative disease or disorder in a subject having or susceptibleto having such a disease or disorder, by administering to the subject atherapeutically effective amount of one or more compounds as describedabove. In one embodiment, the treatment is preventative treatment. Inanother embodiment, the treatment is palliative treatment. In anotherembodiment, the treatment is restorative treatment.

1. Diseases or Conditions

The compound of the present disclosure for inhibiting RIPK2 and c-ablactivity is useful for treatment or prevention of a neurodegenerativedisease or disorder. The compound can be used for inhibiting orhindering RIPK2 and c-abl kinase activity, and for treating aneurodegenerative disease or disorder, or for preventing aggravation ofsuch disease. Thus, the present disclosure provides a method forinhibiting or hindering RIPK2 and c-abl activity in a cell, wherein thecell is contacted with an effective amount of a compound of the presentdisclosure. In one embodiment, such cell is present in a subject (forexample, Alzheimer patients). In another embodiment, there is provided amedical use for treating or preventing an inflammatory and/or autoimmunedisease, especially neuroinflammation diseases or disorder in a subject,using the compound according to the present disclosure. The method ofthe present disclosure comprises administering to a subject in need oftreatment or prevention a pharmaceutical composition containing atherapeutically or prophylactically effective amount of RIPK2 and c-ablinhibitor. The inflammatory and autoimmune diseases, especiallyneuroinflammation diseases or disorder includes, but is not limited to,α-synucleinopathy, Parkinson's disease, dementia with Lewy body,multiple system atrophy (MSA), Alzheimer's disease or amyotrophiclateral sclerosis (ALS).

2. Subjects

Suitable subjects to be treated according to the present disclosureinclude mammalian subjects. Mammals according to the present disclosureinclude, but are not limited to, human, canine, feline, bovine, caprine,equine, ovine, porcine, rodents, lagomorphs, primates, and the like, andencompass mammals in utero. Subjects may be of either gender and at anystage of development. In one embodiment, the suitable subject to betreated according to the present disclosure is human.

3. Administration and Dosing

The compounds of the present disclosure are generally administered in atherapeutically effective amount. The compounds of the presentdisclosure can be administered by any suitable route in the form of apharmaceutical composition adapted to such a route, and in a doseeffective for the treatment intended. An effective dosage is typicallyin the range of about 0.001 to about 100 mg per kg body weight per day,preferably about 0.01 to about 50 mg/kg/day, in single or divided doses.Depending on age, species and disease or condition being treated, dosagelevels below the lower limit of this range may be suitable. In othercases, still larger doses may be used without harmful side effects.Larger doses may also be divided into several smaller doses, foradministration throughout the day. Methods for determining suitabledoses are well known in the art to which the present disclosurepertains. For example, Remington: The Science and Practice of Pharmacy,Mack Publishing Co., 20th ed., 2000 can be used.

Pharmaceutical Compositions, Dosage Forms and Administration Routes

For the treatment of the diseases or conditions referred to above, thecompounds described herein or pharmaceutically acceptable salts thereofcan be administered as follows:

Oral Administration

The compounds of the present disclosure may be administered orally,including by swallowing, so that the compound enters thegastrointestinal tract, or absorbed into the blood stream directly fromthe mouth (e.g., buccal or sublingual administration).

Suitable compositions for oral administration include solid, liquid, gelor powder formulations, and have a dosage form such as tablet, lozenge,capsule, granule or powder.

Compositions for oral administration may be formulated as immediate ormodified release, including delayed or sustained release, optionallywith enteric coating.

Liquid formulations can include solutions, syrups and suspensions, whichcan be used in soft or hard capsules. Such formulations may include apharmaceutically acceptable carrier, for example, water, ethanol,polyethylene glycol, cellulose, or an oil. The formulation may alsoinclude one or more emulsifying agents and/or suspending agents.

In a tablet dosage form the amount of drug present may be from about0.05% to about 95% by weight, more typically from about 2% to about 50%by weight of the dosage form. In addition, tablets may contain adisintegrant, comprising from about 0.5% to about 35% by weight, moretypically from about 2% to about 25% of the dosage form. Examples ofdisintegrants include, but are not limited to, lactose, starch, sodiumstarch glycolate, crospovidone, croscarmellose sodium, maltodextrin, ormixtures thereof.

Suitable lubricants, for use in a tablet, may be present in amounts fromabout 0.1% to about 5% by weight, and include, but are not limited to,talc, silicon dioxide, stearic acid, calcium, zinc or magnesiumstearate, sodium stearyl fumarate and the like.

Suitable binders, for use in a tablet, include, but are not limited to,gelatin, polyethylene glycol, sugars, gums, starch, polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropylmethyl cellulose andthe like. Suitable diluents, for use in a tablet, include, but are notlimited to, mannitol, xylitol, lactose, dextrose, sucrose, sorbitol,microcrystalline cellulose and starch.

Suitable solubilizers, for use in a tablet, may be present in amountsfrom about 0.1% to about 3% by weight, and include, but are not limitedto, polysorbates, sodium lauryl sulfate, sodium dodecyl sulfate,propylene carbonate, diethyleneglycol monoethyl ether, dimethylisosorbide, polyethylene glycol (natural or hydrogenated) castor oil,HCOR™ (Nikkol), oleyl ester, Gelucire™, caprylic/caprylic acidmono/diglyceride, sorbitan fatty acid esters, and Solutol HS™.

Parenteral Administration

Compounds of the present disclosure may be administered directly intothe blood stream, muscle, or internal organs. Suitable means forparenteral administration include intravenous, intra-muscular,subcutaneous intraarterial, intraperitoneal, intrathecal, intracranial,and the like. Suitable devices for parenteral administration includeinjectors (including needle and needle-free injectors) and infusionmethods.

Compositions for parenteral administration may be formulated asimmediate or modified release, including delayed or sustained release.Most parenteral formulations are aqueous solutions containingexcipients, including salts, buffering agents and isotonic agents.Parenteral formulations may also be prepared in a dehydrated form (e.g.,by lyophilization) or as sterile non-aqueous solutions. Theseformulations can be used with a suitable vehicle, such as sterile water.Solubility-enhancing agents may also be used in preparation ofparenteral solutions.

Transdermal Administration

Compounds of the present disclosure may be administered topically to theskin or transdermally. Formulations for this topical administration caninclude lotions, solutions, creams, gels, hydrogels, ointments, foams,implants, patches and the like. Pharmaceutically acceptable carriers fortopical administration formulations can include water, alcohol, mineraloil, glycerin, polyethylene glycol and the like. Topical or transdermaladministration can also be performed by electroporation, iontophoresis,phonophoresis and the like.

Compositions for topical administration may be formulated as immediateor modified release, including delayed or sustained release.

Combination Therapy

A pharmaceutical composition according to the present disclosure maycontain one or more additional therapeutic agents, for example, toincrease the efficacy or decrease the side effects. In some embodiments,accordingly, a pharmaceutical composition further contains one or moreadditional therapeutic agents selected from active ingredients useful totreat or inhibit diseases mediated directly or indirectly by RIPKs andc-abl kinase. Examples of such active ingredients are, withoutlimitation, agents to treat inflammatory and autoimmune diseases ordisorder.

References for Preparing Pharmaceutical Compositions

Methods for preparing pharmaceutical compositions for treating orpreventing a disease or condition are well known in the art to which thepresent disclosure pertains. For example, based on Handbook ofPharmaceutical Excipients (7^(th) ed.), Remington: The Science andPractice of Pharmacy (20^(th) ed.), Encyclopedia of PharmaceuticalTechnology (3^(rd) ed.), or Sustained and Controlled Release DrugDelivery Systems (1978), pharmaceutically acceptable excipients,carriers, additives and so on can be selected and then mixed with thecompounds of the present disclosure for making the pharmaceuticalcompositions.

The present disclosure provides a compound having variouspharmacological effects by inhibiting RIPK2 and c-abl activity, apharmaceutical composition having the compound as an effective agent, amedical use, particularly for treating a neurodegenerative disease ordisorder, of the compound, and a method of treatment or preventioncomprising administering the compound to a subject in need of suchtreatment or prevention. The compounds of the present disclosure andpharmaceutically acceptable salts thereof have good safety and highselectivity for RIPK2 and c-abl, and thus exhibit superior property as adrug.

DETAILED DESCRIPTION

Hereinafter, the present disclosure is described in considerable detailwith examples to help those skilled in the art understand the presentdisclosure. However, the following examples are offered by way ofillustration and are not intended to limit the scope of the invention.It is apparent that various changes may be made without departing fromthe spirit and scope of the invention or sacrificing all of its materialadvantages.

Synthesis of Formula (I) Compounds

Synthetic methods from A to S were used to prepare the compounds of thefollowing. Below, the illustrating synthetic examples of some compoundsof the present disclosure are described, and other compounds can beprepared by the similar method to the one described below with differentstarting or reacting materials.

Synthetic Method A

Example 1.(2-amino-6-bromoimidazo[1,2-a]pyridin-3-yl)(cyclopropyl)methanone

To a solution of cyclopropanecarboxylic acid (3.17 g, 36.78 mmol, 2.91mL, 1.3 eq) in DMF (50 mL) was added EDCI (6.51 g, 33.95 mmol, 1.2 eq),HOBt (4.59 g, 33.95 mmol, 1.2 eq) and TEA (8.59 g, 84.89 mmol, 11.82 mL,3 eq). The mixture was stirred at 15° C. for 1 hr. then added6-bromoimidazo[1,2-a]pyridin-2-amine (6 g, 28.30 mmol, 1 eq). The finalmixture was stirred at 15° C. for 18 hr. The mixture was poured intowater (200 mL) and extracted with ethyl acetate (300 mL*3), the organicphase was washed with brine (500 mL*2) and dried with anhydrous sodiumsulfate (Na₂SO₄), filtered and concentrated in vacuum. The residue waspurified by trituration with ethyl acetate (50 mL), filtered and thefilter cake was concentrated. Example 1 (2.4 g, 8.25 mmol, 30.28% yield,96.3% purity) was obtained as yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (d, J=1.2 Hz, 1H), 7.60 (dd, J=2.1, 9.3Hz, 1H), 7.32 (d, J=9.3 Hz, 1H), 6.62 (s, 2H), 2.46-2.37 (m, 1H),1.02-0.90 (m, 4H); LCMS (electrospray) m/z 282.10 (M+2H)+.

Synthetic Method B

Example 6.1-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one

Step 1) 1-(2-amino-6-bromoimidazo[1,2-a]pyridin-3-yl)ethan-1-one

To a solution of 6-bromoimidazo[1,2-a]pyridin-2-amine (260 mg, 1.23mmol, 1 eq) in DCM (20 mL) were added EDCI (358 mg, 1.84 mmol, 1.5 eq),HOBt (249 mg, 1.84 mmol, 1.5 eq), TEA (186 mg, 1.84 mmol, 256 μL, 1.5eq), the mixture was stirred at 25° C. for 1 hr, then acetic acid (81mg, 1.35 mmol, 1.1 eq) was added. The mixture was stirred at 25° C. for12 hr. The reaction mixture was concentrated under reduced pressure toremove DCM solution to give a residue. The crude product was purified bysilica gel chromatography (product came out at hexane/ethyl acetate=1/2)to afford Compound 1 (177 mg, 0.67 mmol, 57% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.66 (s, 1H), 7.61 (dd, J=9.3, 2.2 Hz, 1H),7.33 (d, J=9.3 Hz, 1H), 6.51 (s, 2H), 2.43 (s, 3H).

Step 2)1-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one

To a solution of Compound 1 (150 mg, 0.590 mmol, 1 eq) in dioxane (6 mL)and H₂O (2 mL) were added (3-fluoro-2-methylphenyl)boronic acid (136 mg,0.883 mmol, 1.5 eq), Na₂CO₃ (125 mg, 1.179 mmol, 2.0 eq), Pd(dppf)Cl₂(43 mg, 0.06 mmol, 0.1 eq) at the room temperature and then heated at120° C. under the microwaves for 30 min, cooled down to the roomtemperature, filtered through a celite pad to remove solids, andpartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate solution. The organic layer was washed with saturatedaqueous sodium chloride solution, separated, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel chromatography (hexane/ethyl acetate=1/1) to afford Example 6(122 mg, 0.430 mmol, 73% yield) as an ivory solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 7.51 (dd, J=9.2, 1.8 Hz, 1H),7.41 (d, J=8.2 Hz, 1H), 7.38-7.29 (m, 1H), 7.23 (t, J=8.5 Hz, 1H), 7.16(d, J=7.1 Hz, 1H), 6.47 (s, 2H), 2.44 (s, 3H), 2.16 (d, J=2.2 Hz, 3H);LCMS (electrospray) m/z 284.10 (M+H)+.

Synthetic Method C

Example 24.(2-((2-(dimethylamino)ethyl)amino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

To a solution of Example 5 (100 mg, 0.30 mmol, 1 eq) in DMF (1.5 mL)were added 2-bromo-N,N-dimethylethan-1-amine·HBr (105 mg, 0.45 mmol, 1.5eq), K₂CO₃ (124 mg, 0.90 mmol, 3 eq) and TBAB (9.6 mg, 0.03 mmol, 0.1eq). The reaction mixture was heated to 100° C. under microwave for 30min. The reaction mixture was diluted with water 10 mL and extractedwith ethyl acetate (10 mL*2). The combined organic layers were washedwith brine (10 mL), dried over Na₂SO₄, filtered and the filtrate wasconcentrated. The residue was purified by silica gel columnchromatography (0 to 20% gradient MeOH in DCM) to obtain Example 24 (10mg, 8.3% yield).

¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 8.22-8.09 (m, 2H), 7.44-7.40(m, 1H), 7.35-7.28 (m, 1H), 7.24-7.12 (m, 1H), 5.37-5.16 (m, 1H), 4.54(s, 2H), 4.09 (d, J=4.9 Hz, 2H), 3.17 (d, J=3.8 Hz, 6H), 2.83-2.66 (m,4H), 2.33-2.08 (m, 3H), 1.96 (dtd, J=23.5, 6.8, 3.2 Hz, 1H), 1.33-1.23(m, 1H); LCMS (electrospray) m/z 399.2 (M+H)+.

Synthetic Method D

Example 28.(2-amino-6-(5-methylthiazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

Step 1)2,2,2-trifluoro-N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-2-yl)acetamide

To a solution ofN-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (1.0 g,3.24 mmol, 1 eq) in DMSO (30 mL) were added Bis(pinacolato)diboron (1.0g, 4.21 mmol, 1.3 eq), Pd(dppf)Cl₂ (234 mg, 0.32 mmol, 0.1 eq), KOAc(953 mg, 9.72 mmol, 3 eq) at the room temperature and then heated at 90°C. for 7 hr, cooled down to the room temperature, filtered through acelite pad to remove solids, and partitioned between ethyl acetate andsaturated aqueous sodium bicarbonate solution. The organic layer waswashed with saturated aqueous sodium chloride solution, separated, driedover anhydrous MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by silica gel chromatography (hexane/ethyl acetate=1/2) toafford Compound 2 (602 mg, 1.69 mmol, 52.4% yield) as beige solid.

Step 2) 6-(5-methylthiazol-4-yl)imidazo[1,2-a]pyridin-2-amine

To a solution of 4-bromo-5-methylthiazole (200 mg, 1.12 mmol, 1 eq) indioxane (4 mL) and H₂O (1 mL) were added Compound 2 (598.35 mg, 1.68mmol, 1.5 eq), Na₂CO₃ (238.11 mg, 2.25 mmol, 2 eq), Pd(dppf)Cl₂ (82.19mg, 112.33 μmol, 0.1 eq), then the mixture was stirred at 90° C. for 16hours under N₂. The reaction mixture was concentrated under reducedpressure to remove H₂O and dioxane solution to give the residue. Theresidue was purified by reversed-phase flash chromatography (MeCN/H₂O,0.05% TFA, 25%˜30%) to give product. Compound 3 (80 mg, 347.39 μmol,30.93% yield) was obtained as a yellow solid.

Step 3)(2-amino-6-(5-methylthiazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

To a solution of (1S,2S)-2-fluorocyclopropane-1-carboxylic acid (31.64mg, 303.97 μmol, 1 eq) in DCM (2 mL) was added EDCI (69.93 mg, 364.76μmol, 1.2 eq), HOBt (49.29 mg, 364.76 μmol, 1.2 eq), TEA (92.27 mg,911.90 μmol, 126.92 μL, 3 eq), the mixture was stirred at 25° C. for 1hr, then were added Compound 3 (70 mg, 303.97 μmol, 1 eq). The mixturewas stirred at 25° C. for 11 hr. The reaction mixture was concentratedunder reduced pressure to remove DCM solution to give a residue. Theresidue was purified by prep-HPLC (column: Waters Xbridge 150*25 mm*5um; mobile phase: [water (0.05% ammonia hydroxide v/v)-ACN]; B %:15%-45%, 10 min). Example 28 (53 mg, 167.53 μmol, 55.12% yield) wasobtained as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.01-9.88 (m, 1H), 8.99 (br d, J=0.9 Hz,1H), 7.91-7.84 (m, 1H), 7.44 (br d, J=9.0 Hz, 1H), 6.68 (br s, 2H),5.29-5.07 (m, 1H), 2.68-2.58 (m, 5H), 1.93-1.84 (m, 1H), 1.20-1.08 (m,1H); LCMS (electrospray) m/z 317.20 (M+H)+.

Synthetic Method E

Example 33.N-(3-acetyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamideand Example 37.N-acetyl-N-(3-acetyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamide

To a solution of Example 6 (250 mg, 0.88 mmol, 1 eq) in DCM (10 mL) wereadded T₃P 50% solution (842 mg, 1.32 mmol, 1.5 eq), TEA (295 mg, 2.91mmol, 406 μL, 3.3 eq), the mixture was stirred at 0° C. for 1 hr, thenacetic acid (132 mg, 2.21 mmol, 2.5 eq) was added. The mixture wasstirred at 25° C. for 15 hr. The reaction mixture was concentrated underreduced pressure to remove DCM solution to give a residue. The crudeproduct was purified by silica gel chromatography (hexane/ethylacetate=1/2) to afford Example 33 (24.9 mg, 0.077 mmol, 8.7% yield) andExample 37 (81.7 mg, 0.222 mmol, 25.3% yield) as a white solid.

Example 33; ¹H NMR (400 MHz, DMSO-d₆) δ 10.51 (s, 1H), 9.51 (s, 1H),7.81 (d, J=9.3 Hz, 1H), 7.68 (dd, J=9.1, 1.9 Hz, 1H), 7.37 (dd, J=14.0,8.0 Hz, 1H), 7.28 (t, J=8.5 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 2.44 (s,3H), 2.22-2.12 (m, 6H); LCMS (electrospray) m/z 326.10 (M+H)+.

Example 37; ¹H NMR (400 MHz, DMSO-d₆) δ 1H NMR (400 MHz, DMSO-d6) δ 9.57(d, J=1.1 Hz, 1H), 7.99-7.91 (m, 1H), 7.80 (dd, J=9.1, 1.9 Hz, 1H),7.44-7.35 (m, 1H), 7.34-7.26 (m, 1H), 7.23 (d, J=7.7 Hz, 1H), 2.37 (s,3H), 2.35 (s, 6H), 2.20 (d, J=2.7 Hz, 3H); LCMS (electrospray) m/z368.10 (M+H)+.

Synthetic Method F

Example 54.(6-(3-fluoro-2-methylphenyl)-2-(methylamino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

To a solution of Example 5 (50 mg, 0.15 mmol, 1 eq) in THF (0.8 mL) wereadded 2M LDA solution in THF (113 μl, 0.225 mmol, 1.5 eq) dropwise at−78° C. After 30 min, Mel (20 μl, 0.3 mmol, 2 eq) was added. Thereaction mixture was stirred at −78° C. for 2 h. Then the mixture wasdiluted with water 10 mL and extracted with ethyl acetate (10 mL*2). Thecombined organic layers were washed with brine (10 mL), dried overNa₂SO₄, filtered and the filtrate was concentrated. The residue waspurified by silica gel column chromatography (0 to 10% gradient MeOH inDCM) to obtain Example 54 (3 mg, 5.8% yield) was obtained.

¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 7.59-7.53 (m, 3H), 7.35 (dd,J=13.7, 8.2 Hz, 1H), 7.27-7.18 (m, 3H), 5.28-5.08 (m, 1H), 4.80 (s, 1H),3.07 (d, J=4.4 Hz, 3H), 2.31 (d, J=18.7 Hz, 1H), 2.18 (d, J=2.2 Hz, 3H),1.91-1.76 (m, 1H), 1.48 (s, 1H), 1.17-1.08 (m, 1H); LCMS (electrospray)m/z 342.10 (M+H)+.

Synthetic Method G

Example 55.(2-(dimethylamino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl)methanone

To a solution of Example 5 (50 mg, 0.15 mmol, 1 eq) in DMF (0.8 mL) wereadded NaH (9 mg, 0.375 mmol, 2.5 eq) portion-wise at 0° C. After 30 min,Mel (30 μl, 0.45 mmol, 3 eq) was added. The reaction mixture was stirredat 0° C. for 2 h. Then the mixture was diluted with water 10 mL andextracted with ethyl acetate (10 mL*2). The combined organic layers werewashed with brine (10 mL), dried over Na₂SO₄, filtered and the filtratewas concentrated. The residue was purified by silica gel columnchromatography (0 to 8% gradient MeOH in DCM) to obtain Example 55 (18mg, 33.7% yield) was obtained.

¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (t, J=1.4 Hz, 1H), 7.70-7.63 (m, 2H),7.35 (dd, J=13.7, 8.2 Hz, 1H), 7.26 (t, J=8.5 Hz, 1H), 7.16 (d, J=7.7Hz, 1H), 5.02 (dd, J=67.3, 1.9 Hz, 1H), 3.07 (d, J=12.6 Hz, 6H), 2.16(d, J=2.2 Hz, 3H), 1.73-1.63 (m, 1H), 1.50 (td, J=12.9, 6.4 Hz, 1H);LCMS (electrospray) m/z 356.10 (M+H)+.

Synthetic Method H

Example 70. tert-butyl(6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)carbamate

Step 1) tert-butyl(6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)dicarbamate

To a solution of Example 5 (500 mg, 1.52 mmol, 1 eq) in THF (7 mL) wereadded TEA (0.414 mL, 3.04 mmol, 2 eq) and DMAP (92 mg, 0.76 mmol, 0.5eq) at the room temperature and then cooled to 0° C. Then, Boc anhydride(499 mg, 2.29 mmol, 1.5 eq) was added slowly to reaction mixture,stirred at the room temperature for 1 hr. The reaction mixture wasextracted with ethyl acetate and washed with water, separated, driedover anhydrous MgSO₄, filtered, and concentrated in vacuo. The residuewas purified by silica gel chromatography (product came out athexane/ethyl acetate=1/2) to afford Compound 4 (720 mg, 1.36 mmol, 89.8%yield) as a white solid.

Step 2) tert-butyl(6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)carbamate

To a solution of Compound 4 (70 mg, 0.132 mmol, 1 eq) in DCM (1.30 mL)were cooled to 0° C. then TFA (0.101 mL, 1.32 mmol, 10 eq) was addeddropwise. The reaction mixture was stirred at rt for 30 min. After theCompound 4 was consumed, the reaction mixture was concentrated andneutralized with saturated aqueous sodium bicarbonate solution. Thereaction mixture was extracted with ethyl acetate, separated, dried overanhydrous MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (product came out at hexane/ethylacetate=4/6) to afford Example 70 (20 mg, 0.046 mmol, 35% yield) as anivory solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (s, 1H), 9.47 (d, J=1.2 Hz, 1H), 7.80(d, J=9.2 Hz, 1H), 7.68 (dd, J=9.6, 2.0 Hz, 1H), 7.38-7.33 (m, 1H), 7.27(t, J=8.8 Hz, 1H), 7.20 (d, J=7.6 Hz, 1H), 5.06-4.83 (m, 1H), 2.91-2.83(m, 1H), 2.17 (d, J=2.0 Hz, 3H), 1.91-1.80 (m, 1H), 1.46 (s, 9H),1.28-1.21 (m, 1H); LCMS (electrospray) m/z 428.20 (M+H)+.

Synthetic Method I

Example 71.(6-(3-fluoro-2-methylphenyl)-2-(pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

To a solution of Example 5 (200 mg, 611.01 μmol, 1 eq) in toluene (3 mL)was added DIPEA (157.94 mg, 1.22 mmol, 212.85 μL, 2 eq), DMAP (7.46 mg,61.10 μmol, 0.1 eq) and 1,4-dibromobutane (791.55 mg, 3.67 mmol, 442.21μL, 6 eq) under N₂. The reaction mixture was stirred at 110° C. for 20hr. Water (15 mL) was added and the aqueous phase was extracted withEtOAc (10 mL*2). The combined organic phase was washed with saturatedbrine (10 mL*2) and concentrated in vacuum. The crude product waspurified by reversed-phase flash chromatography (MeCN/H₂O, 0.05% FA,70%˜85%) to give Example 71 (19.8 mg, 50.20 μmol, 8.22% yield, 96.7%purity) as a light yellow solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.64-9.51 (m, 1H), 8.44 (br s, 1H),7.64-7.55 (m, 2H), 7.42-7.30 (m, 1H), 7.29-7.22 (m, 1H), 7.17 (d, J=7.2Hz, 1H), 5.37-4.94 (m, 1H), 4.05-3.73 (m, 2H), 2.19 (br s, 1H), 2.16 (d,J=2.3 Hz, 3H), 2.08 (s, 2H), 2.04-1.96 (m, 2H), 1.92 (br dd, J=3.4, 6.3Hz, 1H), 1.87-1.79 (m, 2H), 1.30-1.11 (m, 1H); LCMS (electrospray) m/z382.00 (M+H)+.

Synthetic Method J

Example 87.(6-(3-fluoro-2-methylphenyl)-2-((2-(methylamino)ethyl)amino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

Step 1) tert-butyl(2-((6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)amino)ethyl)(methyl)carbamate

To a solution of Example 70 (300 mg, 0.701 mmol, 1.5 eq) in THF (3 mL)were added PPh₃ (183 mg, 0.701 mmol, 1.5 eq) and tert-butyl(2-hydroxyethyl)(methyl)carbamate (81 mg, 0.467 mmol, 1 eq) at the roomtemperature and then cooled to 0° C. Then, DEAD (0.318 mL, 0.701 mmol,1.5 eq) was added slowly to reaction mixture, stirred at the roomtemperature for 3 hr. The reaction mixture was extracted with ethylacetate and washed with water, separated, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (product came out at hexane/ethyl acetate=6/4) toafford Compound 5 (241 mg, 0.412 mmol, 88% yield) as a white solid.

Step 2)(6-(3-fluoro-2-methylphenyl)-2-((2-(methylamino)ethyl)amino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

To a solution of Compound 5 (100 mg, 0.171 mmol, 1 eq) in DCM (1.71 mL)were cooled to 0° C. then TFA (0.261 mL, 3.42 mmol, 20 eq) was addeddropwise. The reaction mixture was stirred at rt for 3 hrs. After theCompound 5 was consumed, the reaction mixture was concentrated andneutralized with saturated aqueous sodium bicarbonate solution. Thereaction mixture was extracted with ethyl acetate, separated, dried overanhydrous MgSO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (product came out atDCM/Methanol=10/1) to afford Example 87 (37 mg, 0.096 mmol, 56% yield)as an ivory solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (br s, 1H), 7.57-7.51 (m, 2H),7.36-7.31 (m, 1H), 7.26-7.17 (m, 2H), 5.27-5.07 (m, 1H), 3.58 (q, 6.0Hz, 2H), 2.76 (t, J=6.0 Hz, 2H), 2.63-2.52 (m, 1H), 2.33 (s, 3H), 2.17(d, J=1.6 Hz, 3H), 1.89-1.79 (m, 1H), 1.24-1.10 (m, 1H); LCMS(electrospray) m/z 385.15 (M+H)+.

Synthetic Method K

Example 88.N-(6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)acetamide

To a solution of Example 5 (78 mg, 0.24 mmol, 1 eq) in DCM (3 mL) wereadded acetic anhydride (49 mg, 0.48 mmol, 2.0 eq), DMAP (29 mg, 0.12mmol, 0.5 eq), DIPEA (62 mg, 0.48 mmol, 2.0 eq). The mixture was stirredat 25° C. for 16 hr. Partitioned between DCM and saturated aqueoussodium bicarbonate solution. The organic layer was washed with saturatedaqueous sodium chloride solution, separated, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel chromatography (product came out at hexane/ethyl acetate=1/1)to afford Example 88 (19 mg, 0.051 mmol, 21% yield) as an ivory solid.

¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 9.51 (d, J=1.1 Hz, 1H), 7.83(d, J=8.8 Hz, 1H), 7.70 (dd, J=9.3, 1.6 Hz, 1H), 7.43-7.32 (m, 1H), 7.28(t, J=9.1 Hz, 1H), 7.21 (d, J=7.7 Hz, 1H), 5.12-4.82 (m, 1H), 2.87-2.73(m, 1H), 2.18 (d, J=2.2 Hz, 3H), 2.16 (s, 3H), 1.92-1.75 (m, 1H),1.30-1.13 (m, 1H); LCMS (electrospray) m/z 370.10 (M+H)+.

Synthetic Method L

Example 89.(2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

Step 1)(2-amino-6-bromoimidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

To a solution of 6-bromoimidazo[1,2-a]pyridin-2-amine (5.81 g, 27.4mmol, 1 eq) in DCM (500 mL) was added EDCI (7.88 g, 41.1 mmol, 1.5 eq),HOBt (6.29 g, 41.1 mmol, 1.5 eq), TEA (4.16 g, 41.1 mmol, 5.73 mL, 1.5eq), the mixture was stirred at 25° C. for 1 hr, then were added(1S,2S)-2-fluorocyclopropane-1-carboxylic acid (3.42 g, 32.9 mmol, 1.2eq). The mixture was stirred at 25° C. for 11 hr. The reaction mixturewas concentrated under reduced pressure to remove DCM solution to give aresidue. The crude product was purified by silica gel chromatography(hexane/ethyl acetate=1/2) to afford Example 2 (6.03 g, 19.62 mmol,71.6% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.69 (s, 1H), 7.63 (d, J=9.2 Hz, 1H), 7.34(d, J=10 Hz, 1H), 6.71 (s, 2H), 5.25-5.06 (m, 1H), 2.62-2.51 (m, 1H),1.91-1.80 (m, 1H), 1.18-1.09 (m, 1H); LCMS (electrospray) m/z 299.00(M+H)+.

Step 2)(2-amino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

To a solution of Example 2 (3.0 g, 10.06 mmol, 1 eq) in dioxane (50 mL)were added 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(3.32 g, 13.08 mmol, 1.3 eq), Pd(dppf)Cl₂ (736 mg, 1.00 mmol, 0.1 eq),KOAc (2.96 g, 30.20 mmol, 3 eq) at the room temperature and then heatedat 90° C. for 7 hr, cooled down to the room temperature, filteredthrough a celite pad to remove solids, and partitioned between ethylacetate and saturated aqueous sodium bicarbonate solution. The organiclayer was washed with saturated aqueous sodium chloride solution,separated, dried over anhydrous MgSO₄, filtered, and concentrated invacuo. The residue was purified by silica gel chromatography(hexane/ethyl acetate=1/2) to afford Compound 6 (1.9 g, 5.504 mmol,54.7% yield) as beige color solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.83 (s, 1H), 7.59 (d, J=9.0 Hz, 1H), 7.32(d, J=9.7 Hz, 1H), 6.73 (s, 2H), 5.23-5.05 (m, 1H), 2.51-2.50 (m, 1H),1.90-1.81 (m, 1H), 1.31 (s, 9H), 1.15-1.06 (m, 1H); LCMS (electrospray)m/z 346.10 (M+H)+, 264.10 (M−82)+.

Step 3)(2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

To a solution of Compound 6 (600 mg, 1.738 mmol, 1 eq) in dioxane (7 mL)and water (1.75 mL) were added 5-bromo-4-methyl-1H-indole (365 mg, 1.738mmol, 1 eq), Na₂CO₃ (553 mg, 5.21 mmol, 3 eq), Pd(dppf)Cl₂ (127 mg,0.174 mmol, 0.1 eq) at the room temperature and then heated at 100° C.under the microwaves for 1 h, cooled down to the room temperature,filtered through a celite pad to remove solids, and partitioned betweenethyl acetate and saturated aqueous sodium bicarbonate solution. Theorganic layer was washed with saturated aqueous sodium chloridesolution, separated, dried over anhydrous MgSO₄, filtered, andconcentrated in vacuo. The residue was purified by silica gelchromatography (hexane/ethyl acetate=1/1) to afford Example 89 (121 mg,0.347 mmol, 19.9% yield) as an ivory solid.

¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 9.47 (s, 1H), 7.50 (dd,J=9.1, 1.9 Hz, 1H), 7.41-7.32 (m, 2H), 7.28 (d, J=8.2 Hz, 1H), 6.98 (d,J=8.2 Hz, 1H), 6.53 (d, J=33.0 Hz, 3H), 5.30-4.98 (m, 1H), 2.60-2.49 (m,1H), 2.38 (s, 3H), 1.90-1.68 (m, 1H), 1.11-0.96 (m, 1H); LCMS(electrospray) m/z 349.10 (M+H)+.

Synthetic Method M

Example 99.(2-amino-8-fluoro-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

Step 1) N-(5-bromo-3-fluoropyridin-2-yl)-4-methylbenzenesulfonamide

To a solution of 5-bromo-3-fluoropyridin-2-amine (10 g, 52.36 mmol, 1eq) in pyridine (100 mL) was added TsCl (10.98 g, 57.59 mmol, 1.1 eq) at20° C. The mixture was stirred at 90° C. for 16 hr. The mixture wasdiluted with NaHCO₃ (200 mL) and extracted with ethyl acetate (300 mL).The organic layer was concentrated. The residue was purified by columnchromatography (SiO₂, petroleum ether/ethyl acetate=5/1 to 3/1).Compound 7 (10 g, 28.97 mmol, 55.33% yield) was obtained as yellowsolid.

Step 2) (E)-2-(5-bromo-3-fluoro-2-(tosylimino)pyridin-1(2H)-yl)acetamide

To a solution of Compound 7 (9 g, 26.07 mmol, 1 eq) in DMF (10 mL) wasadded DIPEA (3.71 g, 28.68 mmol, 5.00 mL, 1.1 eq) and 2-bromoacetamide(3.96 g, 28.68 mmol, 1.1 eq). The mixture was stirred at 20° C. for 16hr. The mixture was concentrated. Compound 8 (10 g, crude) was obtainedas brown solid.

Step 3)N-(6-bromo-8-fluoroimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide

To a solution of Compound 8 (5 g, 12.43 mmol, 1 eq) in DCE (10 mL) wasadded TFAA (31.33 g, 149.17 mmol, 20.75 mL, 12 eq). The mixture wasstirred at 60° C. for 3 hr. The mixture was neutralized with saturatedNaHCO₃ and extracted with ethyl acetate (300 mL). The organic layer wasconcentrated. The residue was purified by reversed-phase flashchromatography (0.1% FA condition, 5-70% water/MeCN) and lyophilized togive Compound 9 (2 g, 6.13 mmol, 24.67% yield) as yellow solid.

Step 4)8-fluoro-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-amine

To a solution of Compound 9 (0.5 g, 1.53 mmol, 1 eq) in dioxane (4 mL)and H₂O (1 mL) was added (3-fluoro-2-methylphenyl)boronic acid (283.30mg, 1.84 mmol, 1.2 eq), Pd(dppf)Cl₂ (112.21 mg, 153.35 μmol, 0.1 eq) andNa₂CO₃ (487.61 mg, 4.60 mmol, 3 eq). The mixture was stirred at 90° C.for 16 hr and concentrated. The residue was purified by reversed-phaseflash chromatography (0.1% FA condition, 5-70% water/MeCN) andlyophilized to give Compound 10 (0.35 g, 1.35 mmol, 88.03% yield) aswhite solid.

Step 5)(2-amino-8-fluoro-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

To a solution of Compound 10 (60.22 mg, 578.58 μmol, 1 eq) in DCM (4 mL)was added EDCI (133.10 mg, 694.30 μmol, 1.2 eq), HOBt (93.82 mg, 694.30μmol, 1.2 eq) and TEA (70.26 mg, 694.30 μmol, 96.64 μL, 1.2 eq). Themixture was stirred at 20° C. for 1 hr, then(1S,2S)-2-fluorocyclopropane-1-carboxylic acid (0.15 g, 578.58 μmol, 1eq) was added. The mixture was stirred at 20° C. for 15 hr andconcentrated. The residue was purified by reversed-phase flashchromatography (0.1% FA condition, 5-70% H₂O/MeCN) and lyophilized togive Example 99 (68 mg, 185.50 μmol, 32.06% yield, 94.2% purity, whitesolid).

¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H), 7.62-7.59 (m, 1H), 7.36-7.19(m, 3H), 6.87 (s, 1H), 5.29-5.10 (m, 1H), 2.61-2.52 (m, 1H), 2.19 (s,3H), 1.89-1.84 (m, 1H), 1.17-1.13 (m, 1H); LCMS (electrospray) m/z346.10 (M+H)+.

Synthetic Method N

Example 107.2-amino-N-cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide

Step 1) 6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-amine

To a solution of 6-bromoimidazo[1,2-a]pyridin-2-amine (324 mg, 1.53mmol, 1 eq) in dioxane (4 mL) and H₂O (1 mL) was added(3-fluoro-2-methylphenyl)boronic acid (283.30 mg, 1.84 mmol, 1.2 eq),Pd(dppf)Cl₂ (112.21 mg, 153.35 μmol, 0.1 eq) and Na₂CO₃ (487.61 mg, 4.60mmol, 3 eq). The mixture was stirred at 90° C. for 16 hr. The mixturewas concentrated. The residue was purified by reversed-phase flashchromatography (0.1% FA condition, 5-70% H₂O/MeCN) and lyophilized togive Compound 11 (107 mg, 1.07 mmol, 70.00% yield) as white solid.

Step 2) Di-tert-butyl(6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)carbamate

To a solution of Compound 11 (500 mg, 2.07 mmol, 1 eq) in THF (10 mL)were added TEA (0.577 mL, 4.14 mmol, 2 eq) and DMAP (126 mg, 1.03 mmol,0.5 eq) at the room temperature and then cooled to 0° C. Then, Bocanhydride (903 mg, 4.14 mmol, 2.0 eq) was added slowly to reactionmixture and the mixture was stirred at the room temperature for 1 hr.The reaction mixture was extracted with ethyl acetate and washed withwater, separated, dried over anhydrous MgSO₄, filtered, and concentratedin vacuo. The residue was purified by silica gel chromatography(hexane/ethyl acetate=6/4) to afford Compound 12 (445 mg, 1.00 mmol, 48%yield) as a white solid.

Step 3)2-(di(tert-butoxycarbonyl)amino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxylicacid

To a solution of Compound 12 (200 mg, 0.453 mmol, 1 eq) in THF (2.26 mL)was cooled to −78° C. and was added LDA (0.906 mL, 1.81 mmol, 4 eq)dropwise then stirred at the same temperature for 30 min. Dry ice wasadded portion-wise, the reaction mixture was stirred at −78° C. for 2hrs. Then the reaction mixture was quenched with ice, extracted withDCM, the combined organic phase was washed with water (100 mL), driedover anhydrous MgSO₄, filtered, and concentrated in vacuo. The crudeproduct was purified by silica gel chromatography (DCM/Methanol=10/1) toafford Compound 13 (81 mg, 0.166 mmol, 36% yield) as a white solid.

Step 4) Di-tert-butyl(3-(cyclopropyl(methyl)carbamoyl)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)carbamate

To a solution of Compound 13 (81 mg, 0.164 mmol, 1 eq) in DMF (0.8 mL)were added N-methylcyclopropanamine (17 mg, 0.247 mmol, 1.5 eq), EDCI(62 mg, 0.328 mmol, 2.0 eq), HOBt (44 mg, 0.328 mmol, 2 eq), TEA (0.068mL, 0.492 mmol, 3 eq), the mixture was stirred at 50° C. for 2 hr. Thereaction mixture was extracted with ethyl acetate and the combinedorganic phase was washed with aqueous saturated sodium chloride solution(100 mL), dried over anhydrous MgSO₄, filtered, and concentrated invacuo. The crude product was purified by silica gel chromatography(hexane/ethyl acetate=6/4) to afford Compound 14 (49 mg, 0.090 mmol, 55%yield) as a white solid.

Step 5)2-amino-N-cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide

To a solution of Compound 14 (45 mg, 0.083 mmol, 1 eq) in DCM (0.4 mL)was added 4 N HCl in dioxane (0.2 mL, 0.835 mmol, 10 eq) dropwise. Thereaction mixture was stirred at rt for 1 hr. After the Compound 14 wasconsumed, the reaction mixture was concentrated and neutralized withsaturated aqueous sodium bicarbonate solution. The reaction mixture wasextracted with ethyl acetate, separated, dried over anhydrous MgSO₄,filtered, and concentrated in vacuo. The residue was purified by silicagel chromatography (DCM/Methanol=8/1) to afford Example 107 (22 mg,0.065 mmol, 78% yield) as an ivory solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.35-7.25 (m, 3H), 7.21 (t,J=9.0 Hz, 1H), 7.14 (d, J=7.2 Hz, 1H), 5.71 (s, 2H), 2.94 (s, 3H),2.91-2.84 (m, 1H), 2.16 (s, 3H), 0.60-0.51 (m, 4H); LCMS (electrospray)m/z 339.10 (M+H)+.

Synthetic Method O

Example 112.N′-acetyl-2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carbohydrazide

To a solution of Compound 13 (84 mg, 0.155 mmol, 1 eq) in DCM (0.8 mL)were added acetohydrazide (13.7 mg, 0.186 mmol, 1.2 eq), EDCI (46 mg,0.232 mmol, 1.5 eq), HOBt (31.4 mg, 0.232 mmol, 1.5 eq) and the mixturewas stirred at 25° C. for 16 hr. The reaction mixture was extracted withDCM (3 mL) and the combined organic phase was washed with aqueous 1N HClsolution (3 mL), dried over anhydrous MgSO₄, filtered, and concentratedin vacuo. The crude product was purified by silica gel chromatography(Dichloromethane/Methanol=8/2) to afford Example 112 (4.6 mg, 0.013mmol, 8.6% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.82 (s, 1H), 9.10 (s, 1H), 9.06 (t, J=1.4Hz, 1H), 7.39 (d, J=1.1 Hz, 2H), 7.33-7.16 (m, 3H), 6.18 (s, 2H), 2.16(d, J=2.2 Hz, 3H), 1.90 (s, 3H); LCMS (electrospray) m/z 342.10 (M+H)+.

Synthetic Method P

Example 135. methyl2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxylate

Step 1)N-(6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamide

To a solution of Compound 11 (58 mg, 0.24 mmol, 1 eq) in DCM (3 mL) wereadded acetic anhydride (49 mg, 0.48 mmol, 2.0 eq), DMAP (29 mg, 0.12mmol, 0.5 eq), DIPEA (62 mg, 0.48 mmol, 2.0 eq). The mixture was stirredat 25° C. for 16 hr. The mixture was partitioned between DCM andsaturated aqueous sodium bicarbonate solution. The organic layer waswashed with saturated aqueous sodium chloride solution, separated, driedover anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residuewas purified by silica gel chromatography (hexane/ethyl acetate=1/1) toafford Compound 15 (38 mg, 0.13 mmol, 56% yield) as an ivory solid

Step 2)N-(3-bromo-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamide

To a solution of Compound 15 (30 mg, 0.105 mmol, 1 eq) in MeCN (1 mL)were added N-bromosuccinimide (18.6 mg, 0.105 mmol, 1.0 eq) and themixture was stirred at 0° C. for 2 hr. The reaction mixture wasextracted with DCM (3 mL) and the combined organic phase was washed withH₂O, dried over anhydrous MgSO₄, filtered, and concentrated in vacuo.The Compound 16 (32 mg, 0.09 mmol, 86% yield) was obtained as an ivorysolid.

Step 3) methyl2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxylate

To a solution of Compound 16 (300 mg, 828.28 μmol, 1 eq) in MeOH (10 mL)was added TEA (252 mg, 2.48 mmol, 346 μL, 3 eq) and Pd(dppf)Cl₂ (61 mg,82.83 μmol, 0.1 eq) and the reaction mixture was stirred at 80° C. for12 hrs under CO atmosphere (50 psi). The reaction mixture was filteredand concentrated to give a residue. The residue was purified by columnchromatography (silica gel, petroleum ether:ethyl acetate=1:1 to 0:1)and Prep-HPLC (column: Waters Xbridge 150*25 mm*5 um; mobile phase:[water (10 mM NH₄HCO₃)-ACN]; B %: 30%-63%, 9 min), followed bylyophilization. Example 135 (5.2 mg, 17.37 μmol, 2.10% yield, 100%purity) was obtained as white solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (br s, 1H), 7.48-7.43 (m, 1H),7.42-7.38 (m, 1H), 7.37-7.30 (m, 1H), 7.27-7.21 (m, 1H), 7.17 (d, J=7.7Hz, 1H), 6.40 (s, 2H), 3.82 (s, 3H), 2.17 (d, J=2.3 Hz, 3H); LCMS(electrospray) m/z 300.10 (M+H)+

Synthetic Method Q

Example 148.(2-amino-6-((3-fluoro-2-methylphenyl)amino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

Step 1)2,2,2-trifluoro-N-(6-((3-fluoro-2-methylphenyl)amino)imidazo[1,2-a]pyridin-2-yl)acetamide

To a solution ofN-(6-bromoimidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (500 mg,1.62 mmol, 1 eq) and 3-fluoro-2-methylaniline (243.74 mg, 1.95 mmol,221.58 μL, 1.2 eq) in 1,4-dioxane (10 mL) was added BrettPhos Pd G3(147.13 mg, 162.31 μmol, 0.1 eq), and t-BuONa (2 M, 1.62 mL, 2 eq). Themixture was stirred at 90° C. for 12 h under N₂. The reaction mixturewas partitioned between ethyl acetate (100 mL*3) and H₂O (100 mL*3). Theorganic phase was separated, washed with NaCl (100 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=3/1 to 0/1). Compound 17 (100 mg, 283.86μmol, 17.49% yield) was obtained as brown gum.

Step 2) N₆-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-2,6-diamine

To a solution of Compound 17 (100 mg, 283.86 μmol, 1 eq) in MeOH (5 mL)and H₂O (1 mL) was added K₂CO₃ (117.69 mg, 851.58 μmol, 3 eq). Themixture was stirred at 70° C. for 12 hr. The reaction mixture waspartitioned between ethyl acetate (50 mL*3) and H₂O (50 mL*3). Theorganic phase was separated, washed with NaCl (50 mL), dried overNa₂SO₄, filtered and concentrated under reduced pressure to give aresidue. The residue was purified by column chromatography (SiO₂,petroleum ether/ethyl acetate=3/1 to 0/1). Compound 18 (20 mg, 78.04μmol, 27.49% yield) was obtained as brown solid.

Step 3)(2-amino-6-((3-fluoro-2-methylphenyl)amino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone

To a solution of Compound 18 (20 mg, 78.04 μmol, 1 eq) and(1S,2S)-2-fluorocyclopropane-1-carboxylic acid (8.12 mg, 78.04 μmol, 1eq) in DCM (3 mL) was added EDCI (14.96 mg, 78.04 μmol, 1 eq) and HOBt(10.55 mg, 78.04 μmol, 1 eq). The mixture was stirred at 25° C. for 12hr. The solvent was evaporated under reduced pressure. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=I/O to 1/1), The crude product was purified by reversed-phaseHPLC (0.1% FA condition). Example 148 (0.5 mg, 1.46 μmol, 1.87% yield)was obtained as brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 9.46-9.28 (m, 1H), 7.57 (s, 1H) 7.37-7.33(m, 1H) 7.33-7.29 (m, 1H), 7.09-7.02 (m, 1H), 6.74-6.70 (m, 1H),6.68-6.65 (m, 1H), 6.42 (br s, 1H), 5.25-5.01 (m, 1H), 2.12 (d, J=1.59Hz, 3H), 1.88-1.75 (m, 1H), 1.14-1.02 (m, 2H); LCMS (electrospray) m/z343.10 (M+H)+.

Synthetic Method R

Example 151. (3S,4R)-4-methyltetrahydrofuran-3-yl2-amino-6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxylate

Step 1)N-(6-(5-chloro-6-fluoro-7-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyridin-2-yl)-2,2,2-trifluoroacetamide

To a mixture of Compound 2 (938 mg, 2.64 mmol, 2 eq) and4-bromo-5-chloro-6-fluoro-7-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole(500 mg, 1.32 mmol, 1 eq) in dioxane (25 mL) and H₂O (5 mL) was addedPd(dppf)Cl₂ (97 mg, 132.00 μmol, 0.1 eq) and Na₂CO₃ (420 mg, 3.96 mmol,3 eq) in one portion at 20° C. under N₂. The mixture was heated to 80°C. and stirred for 3 hours. The reaction mixture was filtered, and thendiluted with H₂O (20 mL) and extracted with ethyl acetate (30 mL*3). Thecombined organic layers were dried over Na₂SO₄, filtered andconcentrated under reduced pressure to give a residue. The residue waspurified by column chromatography (SiO₂, petroleum ether/ethylacetate=20/1 to 1/1). Compound 19 (400 mg, 757.69 μmol, 57.40% yield)was obtained as a red oil.

Step 2)6-(5-chloro-6-fluoro-7-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyridin-2-amine

To a mixture of Compound 19 (350 mg, 662.98 μmol, 1 eq) in MeOH (20 mL)and H₂O (5 mL) was added K₂CO₃ (458 mg, 3.31 mmol, 5 eq) in one portionat 20° C. under N₂. The mixture was heated to 70° C. for 16 hr. Thereaction mixture was diluted with water 20 mL and extracted with ethylacetate (30 mL*3), The combined organic layers were dried over Na₂SO₄,filtered and concentrated under reduced pressure to give a residue. Thecrude product was purified by reversed-phase HPLC (0.1% FA condition).Compound 20 (118 mg, 273.20 μmol, 41.21% yield) was obtained as a brownsolid.

Step 3) (3S,4R)-4-methyltetrahydrofuran-3-yl2-amino-6-(5-chloro-6-fluoro-7-(methylthio)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxylate

To a mixture of Compound 20 (80 mg, 185.22 μmol, 1 eq) and(3S,4R)-4-methyltetrahydrofuran-3-yl (4-nitrophenyl) carbonate (248 mg,926.10 μmol, 5 eq) in THF (10 mL) was added DIPEA (144 mg, 1.11 mmol,193.57 μL, 6 eq) in one portion at 20° C. under N₂. The mixture was thenheated to 80° C. and stirred for 24 hours. The reaction mixture wascooled to 20° C., and then quenched by water (20 mL), then the mixturewas extracted by ethyl acetate (30 mL*3). The combined organic layerswere washed with NaCl solution (30 mL*1), dried over Na₂SO₄, filteredand concentrated under reduced pressure to give a residue. The residuewas purified by column chromatography (SiO₂, petroleum ether/ethylacetate=5/1 to 0/1). Compound 21 (54 mg, crude) was obtained as a yellowoil.

Step 4) (3S,4R)-4-methyltetrahydrofuran-3-yl2-amino-6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxylate

To a mixture of Compound 21 (54 mg, 96.42 μmol, 1 eq) in dioxane (2 mL)was added HCl/dioxane (4 M, 0.5 mL, 20.74 eq) in dropwise at 0° C. underN₂. The mixture was stirred at 0° C. for 0.1 hr. The reaction mixturewas quenched by addition Et₃N/MeOH (0.5 mL/0.5 mL) at 0° C., and thenconcentrated under reduced pressure to give a residue. The crude productwas purified by reversed-phase HPLC (0.1% FA condition). Example 151(5.1 mg, 10.72 μmol, 11.11% yield) was obtained as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.82 (s, 1H) 9.15 (s, 1H) 8.08 (s, 1H) 7.64(d, J=9.11, 1H) 7.53 (d, J=9.05 Hz, 1H) 6.29-6.56 (m, 2H) 5.01-5.10 (m,1H) 3.80-4.03 (m, 4H) 2.56-2.64 (m, 4H) 1.05 (d, J=7.09 Hz, 3H); LCMS(electrospray) m/z 476.00 (M+H)+.

Synthetic Method S

Example 153.(2-amino-5-(6-fluoro-5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)(cyclopropyl)methanone

Step 1)N-(5-bromo-3-(cyclopropanecarbonyl)pyrazolo[1,5-a]pyridin-2-yl)-2,2,2-trifluoroacetamide

To a solution ofN-(5-bromopyrazolo[1,5-a]pyridin-2-yl)-2,2,2-trifluoroacetamide (200 mg,0.65 mmol, 1.0 eq) in DCM (13 mL) were added cyclopropanecarbonylchloride (81 mg, 0.78 mmol, 1.2 eq), TiCl₄ (493 mg, 2.601 mmol, 4.0 eq)at the room temperature and then heated at 80° C. for 16 hr. The mixturewas cooled down to the room temperature, quenched with saturated NaHCO₃and extracted with DCM (3×100 mL). The organic layer was washed withsaturated aqueous sodium chloride solution, separated, dried overanhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue waspurified by silica gel chromatography (hexane/ethyl acetate=3/1) toafford Compound 22 (169 mg, 0.449 mmol, 69% yield) as a brown solid.

¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 1H), 8.84 (dd, J=7.1, 2.2 Hz, 1H),8.38 (d, J=2.2 Hz, 1H), 7.40 (dd, J=7.7, 2.2 Hz, 1H), 2.56-2.48 (m, 1H),1.09-1.00 (m, 2H), 1.00-0.93 (m, 2H).

Step 2)(2-amino-5-(6-fluoro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)(cyclopropyl)methanone

To a solution of Compound 22 (80 mg, 0.21 mmol, 1.0 eq) in dioxane (2mL) and H₂O (1 mL) were added6-fluoro-5-methyl-2-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2H-indazole(115 mg, 0.32 mmol, 1.5 eq), Na₂CO₃ (45 mg, 0.43 mmol, 2.0 eq),Pd(dppf)Cl₂ (16 mg, 0.02 mmol, 0.1 eq) at the room temperature and thenheated at 100° C. for 16 hr. The mixture was cooled down to the roomtemperature, filtered through a celite pad to remove solids, andpartitioned between ethyl acetate and saturated aqueous sodiumbicarbonate solution. The organic layer was washed with aqueoussaturated sodium chloride solution, separated, dried over anhydrousNa₂SO₄, filtered, and concentrated in vacuo. The residue was purified bysilica gel chromatography (hexane/ethyl acetate=1/1) to afford Compound23 (44 mg, 0.101 mmol, 48% yield) as an ivory solid.

¹H NMR (400 MHz, DMSO-d₆) δ 8.67 (d, J=7.7 Hz, 1H), 7.94 (d, J=1.1 Hz,1H), 7.85 (s, 1H), 7.70 (d, J=10.4 Hz, 1H), 7.01 (dd, J=6.7, 2.1 Hz,1H), 6.66 (s, 2H), 5.84 (dd, J=9.9, 2.7 Hz, 1H), 3.94-3.84 (m, 1H),3.84-3.69 (m, 1H), 2.49-2.45 (m, 1H), 2.45-2.30 (m, 1H), 2.24 (d, J=2.7Hz, 3H), 2.13-1.89 (m, 2H), 1.84-1.66 (m, 1H), 1.66-1.50 (m, 2H),1.05-0.91 (m, 2H), 0.91-0.80 (m, 2H).

Step 3)(2-amino-5-(6-fluoro-5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)(cyclopropyl)methanone

To a solution of Compound 23 (40 mg, 0.09 mmol, 1.0 eq) in DCM (1 mL)was added TFA (316 mg, 2.77 mmol, 30.0 eq). The mixture was stirred at25° C. for 3 hr. The reaction mixture was adjusted to pH 7 withsaturated aqueous NaHCO₃ solution. The mixture was diluted with water(20 mL) and extracted with ethyl acetate. The combined organic layerswere washed with brine, dried over Na₂SO₄, filtered and concentratedunder reduced pressure to give a residue. The residue was purified bysilica gel chromatography (hexane/ethyl acetate=1/3) to afford Example153 (21.2 mg, 0.061 mmol, 66% yield) as an ivory solid.

¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 8.66 (d, J=6.6 Hz, 1H), 7.95(s, 1H), 7.81 (s, 1H), 7.42 (d, J=9.9 Hz, 1H), 7.02 (dd, J=7.1, 1.6 Hz,1H), 6.66 (s, 2H), 2.49-2.43 (m, 1H), 2.24 (d, J=2.7 Hz, 3H), 1.03-0.92(m, 2H), 0.92-0.82 (m, 2H); LCMS (electrospray) m/z 350.10 (M+H)+.

Table 1 below shows the compounds of Examples along with generalsynthetic methods used to make the compound and characterization data.

TABLE 1 Compounds of Examples Ex Synthetic # Structure/Name 1H NMR/MS(M + 1) Method  1

¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (d, J = 1.2 Hz, 1H), 7.60 (dd, J = 2.1,9.3 Hz, 1H), 7.32 (d, J = 9.3 Hz, 1H), 6.62 (s, 2H), 2.46-2.37 (m, 1H),1.02-0.90 (m, 4H); LCMS (electrospray) m/z 282.10 (M + 2H)+. A  2

¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 8.43 (d, J = 5.6 Hz, 1H), 8.39(s, 1H), 7.50 (d, J = 1.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.34 (d, J= 5.6 Hz, 1H), 6.53 (NH, 2H), 2.45-2.42 (m, 1H), 2.25 (s, 3H), 0.94-0.88(m, 4H); LCMS (electrospray) m/z 293.10 (M + H)+. B  3

¹H NMR (400 MHz, DMSO-d₆) δ 13.07 (NH, 1H), 9.56 (s, 1H), 7.68 (s, 1H),7.50 (d, J = 1.6 Hz, 1H), 7.44-7.41 (m, 2H), 7.28 (d, J = 8.4 Hz, 1H),6.53 (NH, 2H), 2.46-2.45 (m, 1H), 0.92-0.86 (m, 4H); LCMS (electrospray)m/z 332.10 (M + H)+. B  4

¹H NMR (400 MHz, DMSO-d₆) δ 9.69 (s, 1H), 7.63 (d, J = 9.2 Hz, 1H), 7.34(d, J = 10 Hz, 1H), 6.71 (s, 2H), 5.25-5.06 (m, 1H), 2.62-2.51 (m, 1H),1.91-1.80 (m, 1H), 1.18-1.09 (m, 1H); LCMS (electrospray) m/z 299.00(M + H)+. A  5

¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 7.54 (dd, J = 1.6, 8.8 Hz,1H), 7.43 (d, J = 8.8 Hz, 1H), 7.30 (q, J = 7.6 Hz, 1H), 7.23 (t, J =8.8 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 6.67 (s, 2H), 5.27-5.06 (m, 1H),2.60-2.51 (m, 1H), 2.17 (s, 3H), 1.89-1.78 (m, 1H), 1.14-1.07 (m, 1H);LCMS (electrospray) m/z 328.10 (M + H)+. B  6

¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (brs, 1H), 7.51 (dd, J = 1.2, 8.8 Hz,1H), 7.41 (d, J = 8.0 Hz, 1H), 7.34 (q, J = 7.6 Hz, 1H), 7.23 (t, J =8.4 Hz, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.47 (s, 2H), 2.44 (s, 3H), 2.16(s, 3H); LCMS (electrospray) m/z 284.10 (M + H)+. B  7

¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 7.52 (dd, J = 1.6, 8.8 Hz,1H), 7.41 (d, J = 9.6 Hz, 1H), 7.33 (dd, J = 6.4, 8.4 Hz, 1H), 7.21 (dd,J = 3.2, 10.4 Hz, 1H), 7.12 (dt, J = 2.8, 8.8 Hz, 1H), 6.65 (s, 2H),5.27-5.06 (m, 1H), 2.62-2.53 (m, 1H), 2.27 (s, 3H), 1.89-1.78 (m, 1H),1.13-1.05 (m, 1H); LCMS (electrospray) m/z 328.10 (M + H)+. B  8

¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 7.84 (dd, J = 1.6, 8.8 Hz,1H), 7.58 (dd, J = 0.8 4.8 Hz, 1H), 7.50 (dd, J = 1.2, 3.2 Hz, 1H), 7.42(d, J = 8.8 Hz, 1H), 7.16 (dd, J = 3.6, 5.2 Hz, 1H), 6.69 (s, 2H),5.29-5.06 (m, 1H), 2.63-2.53 (m, 1H), 1.94-1.82 (m, 1H), 1.19-1.07 (m,1H); LCMS (electrospray) m/z 302.05 (M + H)+. B  9

¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (br s, 1H), 11.13 (s, 1H), 8.59 (d, J= 7.2 Hz, 1H), 8.21 (s, 1H), 7.62-7.59 (m, 1H), 7.57-7.52 (m, 1H), 6.91(d, J = 2.0 Hz, 1H), 6.89 (s, 1H), 6.69-6.64 (m, 1H), 5.10-4.80 (m, 1H),2.55 (s, 3H), 2.24-2.06 (m, 1H), 1.82-1.54 (m, 1H), 1.27-1.12 (m, 1H);LCMS (electrospray) m/z 350.1 (M + H)+. B  10

¹H NMR (400 MHz, DMSO-d₆) δ 9.53 (s, 1H), 7.84-7.77 (m, 1H), 7.60 (dd, J= 8.8, 11.6 Hz, 1H), 7.50-7.41 (m, 2H), 7.37 (d, J = 7.6 Hz, 1H), 6.70(s, 2H), 5.28-5.05 (m, 1H), 2.62-2.52 (m, 1H), 1.88-1.77 (m, 1H),1.14-1.04 (m, 1H); LCMS (electrospray) m/z 382.10 (M + H)+. B  11

¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 7.47 (dd, J = 1.6, 8.8 Hz,1H), 7.41 (d, J = 8.8 Hz, 1H), 7.23 (d, J = 6.4 Hz, 1H), 7.17 (t, J =7.2 Hz, 1H), 7.11 (d, J = 6.4 Hz, 1H), 6.63 (s, 2H), 5.28-5.05 (m, 1H),2.63-2.52 (m, 1H), 2.31 (s, 3H), 2.13 (s, 3H), 1.89-1.77 (m, 1H),1.14-1.04 (m, 1H); LCMS (electrospray) m/z 324.10 (M + H)+. B  12

¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (br s, 1H), 8.77-8.76 (m, 1H),8.14-8.07 (m, 2H), 7.77 (br s, 2H), 7.70-7.66 (m, 1H), 7.62 (dd, J =1.6, 8.8 Hz, 1H), 7.45-7.43 (m, 1H), 7.38-7.33 (m, 1H), 7.27-7.19 (m,2H), 2.20 (d, J = 2.0 Hz, 3H); LCMS (electrospray) m/z 347.1 (M + H)+. B 13

¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (br s, 1H), 7.61-7.54 (m, 6H),7.47-7.44 (m, 1H), 7.35-7.30 (m, 1H), 7.25-7.20 (m, 1H), 7.13 (d, J =6.8 Hz, 1H), 5.77 (br s, 2H), 2.15 (d, J = 2.0 Hz, 3H); LCMS(electrospray) m/z 346.1 (M + H)+. B  14

¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (br s, 1H), 7.46 (dd, J = 1.8, 9.0 Hz,1H), 7.38-7.35 (m, 1H), 7.31-7.25 (m, 1H), 7.20-7.16 (m, 1H), 7.10 (d, J= 7.2 Hz, 1H), 6.53 (br s, 2H), 2.43-2.36 (m, 1H),, 2.11 (d, J = 2.0 Hz,3H), 0.94- 0.85 (m, 4H); LCMS (electrospray) m/z 310.1 (M + H)+. B  15

¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 7.51 (dd, J12 = 1.8 Hz, J13 =9.0 Hz, 1H), 7.34-7.32 (m, 2H), 7.15-7.11 (m, 2H), 6.63 (s, 2H),5.24-5.04 (m, 1H), 2.56-2.52 (m, 1H), 2.20 (s, 3 H), 1.86- 1.75 (m, 1H),1.11-1.02 (m, 1H); LCMS (electrospray) m/z 328.10 (M + H)+. B  16

¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H), 7.52 (dd, J12 = 1.8 Hz, J13 =9.0 Hz, 1H), 7.40 (d, J = 10.0 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H),7.14-7.09 (m, 2H), 6.64 (s, 2H), 5.26-5.07 (m, 1H), 2.61-2.53 (m, 1H),2.31 (s, 3H), 2.21 (s, 3H), 1.89- 1.78 (m, 1H), 1.14-1.05 (m, 1H)); LCMS(electrospray) m/z 324.10 (M + H)+. B  17

¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H), 7.46 (dd, J12 = 1.8 Hz, J13 =9.0 Hz, 1H), 7.36 (d, J = 10.0 Hz, 1H), 7.13 (d, J = 7.6 Hz, 2H),7.07-7.05 (m, 1H), 6.59 (s, 2H), 5.23-5.02 (m, 1H), 2.55-2.50 (m, 1H),2.29 (s, 3H), 2.19 (s, 3H), 1.85-1.75 (m, 1H), 1.10-1.09 (m, 1H)); LCMS(electrospray) m/z 324.10 (M + H)+. B  18

¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (s, 1H), 7.46 (d, J = 0.8 Hz, 2H),7.41- 7.34 (m, 1H), 7.23-7.12 (m, 2H), 6.68 (s, 2H), 5.28-5.05 (m, 1H),2.62-2.52 (m, 1H), 2.18 (s, 3H), 1.88-1.77 (m, 1H), 1.14-1.04 (m, 1H);LCMS (electrospray) m/z 328.10 (M + H)+. B  19

¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 7.74 (d, J = 7.6 Hz, 1H), 7.57(d, J = 7.2 Hz, 1H), 7.51 (dd, J = 2.4, 9.6 Hz, 1H), 7.46 (t, J = 7.6Hz, 1H), 7.40 (d, J = 9.6 Hz, 1H), 6.65 (s, 2H), 5.25-5.02 (m, 1H),2.60-2.49 (m, 1H), 2.29 (s, 3H), 1.86-1.73 (m, 1H), 1.12-1.01 (m, 1H);LCMS (electrospray) m/z 378.10 (M + H)+. B  20

¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (br s, 1H), 7.50 (dd, J = 9.0, 1.8 Hz,1H), 7.40-7.38 (m, 1H), 7.37-7.31 (m, 1H), 7.26-7.21 (m, 1H), 7.17 (d, J= 7.2 Hz, 1H), 6.40 (br s, 2H), 3.86-3.78 (m, 1H), 2.28-2.22 (m, 4H),2.17 (d, J = 2.0 Hz, 3H), 2.02-1.91 (m, 1H), 1.83-1.74 (m, 1H); LCMS(electrospray) m/z 324.1 (M + H)+. B  21

¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (s, 1H), 8.22 (s, 1H), 7.82 (s, 1H),7.50 (dd, J = 9.0, 1.8 Hz, 1H), 7.43-7.41 (m, 1H), 7.36-7.30 (m, 1H),7.25-7.20 (m, 1H), 7.16 (d, J = 7.2 Hz, 1H), 6.08 (s, 2H), 3.89 (s, 3H),2.17 (d, J = 2.0 Hz, 3H); LCMS (electrospray) m/z 350.1 (M + H)+. B  22

¹H NMR (400 MHz, DMSO-d₆) δ 9.61 (br s, 1H), 7.51-7.49 (m, 1H),7.41-7.38 (m, 1H), 7.32 (q, J = 7.2 Hz, 1H), 7.25- 7.20 (m, 1H), 7.15(d, J = 7.2 Hz, 1H), 6.21 (br s, 2H), 2.16 (s, 3H), 1.30 (s, 9H); LCMS(electrospray) m/z 326.15 (M + H)+. B  23

¹H NMR (400 MHz, DMSO-d₆) δ 9.55 (br s, 1H), 7.51 (dd, J = 9.0, 1.8 Hz,1H), 7.42-7.39 (m, 1H), 7.36-7.31 (m, 1H), 7.26-7.21 (m, 1H), 7.16 (d, J= 7.2 Hz, 1H), 6.44 (br s, 2H), 2.77 (t, J = 7.0 Hz, 3H), 2.17 (d, J =2.8 Hz, 3H), 1.65- 1.57 (m, 2H), 1.41-1.30 (m, 1H), 0.906 (t, J = 7.4Hz, 3H); LCMS (electrospray) m/z 326.15 (M + H)+. B  24

¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (s, 1H), 8.22-8.09 (m, 2H), 7.44-7.40(m, 1H), 7.35-7.28 (m, 1H), 7.24-7.12 (m, 1H), 5.37-5.16 (m, 1H), 4.54(s, 2H), 4.09 (d, J = 4.9 Hz, 2H), 3.17 (d, J = 3.8 Hz, 6H), 2.83-2.66(m, 4H), 2.33- 2.08 (m, 3H), 1.96 (dtd, J = 23.5, 6.8, 3.2 Hz, 1H),1.33-1.23 (m, 1H); LCMS (electrospray) m/z 399.2 (M + H)+. C  25

¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H), 7.52 (dd, J = 2.0, 8.8 Hz,1H), 7.41 (d, J = 8.4 Hz, 1H), 7.31 (dd, J = 6.4, 8.0 Hz, 1H), 7.21 (dd,J = 2.8, 10.4 Hz, 1H), 7.12 (dt, J = 2.8, 8.0 Hz, 1H), 6.66 (s, 2H),5.10-4.88 (m, 1H), 3.11-3.00 (m, 1H), 2.28 (s, 3H), 1.67-1.53 (m, 1H),1.40-1.29 (m, 1H); LCMS (electrospray) m/z 328.10 (M + H)+. B  26

¹H NMR (400 MHz, DMSO-d₆) δ 9.41 (s, 1H), 7.46 (s, 2H), 7.40-7.33 (m,1H), 7.24-7.12 (m, 2H), 6.69 (s, 2H), 5.10- 4.89 (m, 1H), 3.11-2.99 (m,1H), 2.17 (s, 3H), .1.66-1.54 (m, 1H), 1.39-1.29 (m, 1H); LCMS(electrospray) m/z 328.10 (M + H)+. B  27

¹H NMR (400 MHz, DMSO-d₆) δ 9.90 (s, 1H), 7.85 (dd, J = 2.0, 8.8 Hz,1H), 7.77 (d, J = 1.2 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 6.96 (d, J =3.6 Hz, 1H), 6.67 (s, 2H), 6.62 (dd, J = 1.6, 3.2 Hz, 1H), 5.29-5.05 (m,1H), 2.63-2.53 (m, 1H), 1.95-1.81 (m, 1H), 1.18-1.07 (m, 1H); LCMS(electrospray) m/z 286.10 (M + H)+. B  28

¹H NMR (400 MHz, DMSO-d₆) δ 10.01- 9.88 (m, 1H), 8.99 (br d, J = 0.9 Hz,1H), 7.91-7.84 (m, 1H), 7.44 (br d, J = 9.0 Hz, 1H), 6.68 (br s, 2H),5.29-5.07 (m, 1H), 2.68-2.58 (m, 5H), 1.93-1.84 (m, 1H), 1.20-1.08 (m,1H); LCMS (electrospray) m/z 317.20 (M + H)+. D  29

¹H NMR (400 MHz, DMSO-d₆) δ 9.75- 9.65 (m, 1H), 7.60 (dd, J = 1.9, 9.1Hz, 1H), 7.51 (d, J = 5.1 Hz, 1H), 7.43 (dd, J = 0.7, 9.0 Hz, 1H), 7.04(d, J = 5.1 Hz, 1H), 6.75-6.64 (m, 2H), 5.31-5.05 (m, 1H), 2.62-2.55 (m,1H), 2.30 (s, 3H), 1.95-1.79 (m, 1H), 1.01 (s, 1H); LCMS (electrospray)m/z 316.20 (M + H)+. D  30

¹H NMR (400 MHz, DMSO-d₆) δ 9.76 (s, 1H), 9.06 (s, 1H), 8.26 (s, 1H),7.86 (dd, J12 = 1.8 Hz, J13 = 9.0 Hz, 1H), 7.42 (d, J = 9.6 Hz, 1H),6.72 (s, 2H), 5.09- 4.92 (m, 1H), 3.07-2.99 (m, 1H), 1.63- 1.53 (m, 1H),1.37-1.32 (m, 1H); LCMS (electrospray) m/z 303.00 (M + H)+. D  31

¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H), 7.52 (dd, J = 1.6, 8.8 Hz,1H), 7.43 (d, J = 8.4 Hz, 1H), 7.37 (q, J = 8.4 Hz, 1H), 7.19 (m, 1H),6.68 (s, 2H), 5.29- 5.05 (m, 1H), 2.64-2.53 (m, 1H), 2.21 (d, J = 3.2Hz, 3H), 1.91-1.77 (m, 1H), 1.16-1.04 (m, 1H); LCMS (electrospray) m/z346.10 (M + H)+. B  32

¹H NMR (400 MHz, DMSO-d₆) δ 11.77 (s, 1H), 9.84 (s, 1H), 8.48 (d, J =2.0 Hz, 1H), 8.21 (d, J = 1.6 Hz, 1H), 7.89 (dd, J = 1.6, 8.8 Hz, 1H),7.54 (t, J = 3.2 Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 6.65 (s, 2H), 6.54(q, J = 1.6 Hz, 1H), 5.32- 5.07 (m, 1H), 2.69-2.56 (m, 1H), 1.95- 1.82(m, 1H), 1.16-1.07 (m, 1H); LCMS (electrospray) m/z 336.10 (M + H)+. L 33

¹H NMR (400 MHz, DMSO-d₆) δ 10.50 (s, 1H), 9.50 (s, 1H), 7.81 (d, J =9.2 Hz, 1H), 7.68 (dd, J = 2.4, 9.6 Hz, 1H), 7.37 (m, 1H), 7.27 (t, J =8.0 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 2.44 (s, 3H), 2.17 (d, J = 2.4Hz, 3H), 2.15 (s, 3H); LCMS (electrospray) m/z 326.10 (M + H)+. E  34

¹H NMR (400 MHz, DMSO-d₆) δ 9.59 (s, 1H), 7.61-7.54 (m, 2H), 7.50-7.46(m, 1H), 7.45-7.39 (m, 3H), 6.66 (s, 2H), 5.24-5.04 (m, 1H), 2.58-2.51(m, 1H), 1.85-1.75 (m, 1H), 1.11-1.02 (m, 1H); LCMS (electrospray) m/z330.10 (M + H)+. B  35

¹H NMR (400 MHz, DMSO-d₆) δ 9.48 (s, 1H), 7.50 (dd, J = 9.1, 1.9 Hz,1H), 7.39 (d, J = 9.9 Hz, 1H), 7.32-7.27 (m, 1H), 7.22-7.12 (m, 2H),6.64 (s, 2H), 5.23- 5.03 (m, 1H), 2.58-2.51 (m, 1H), 2.13 (d, J = 2.7Hz, 3H), 1.85-1.75 (m, 1H), 1.10-1.02 (m, 1H); LCMS (electrospray) m/z328.10 (M + H)+. B  36

¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (br s, 1H), 7.56 (dd, J = 8.8, 1.6 Hz,1H), 7.43 (d, J = 8.8 Hz, 1H), 7.37-7.32 (m, 1H), 7.24 (t, J = 9.0 Hz,1H), 7.17 (d, J = 8.0 Hz, 1H), 6.59-6.53 (m, 2H), 5.36-5.33 (m, 1H),3.84-3.73 (m, 2H), 2.77-2.61 (m, 1H), 2.17 (d, J = 2.4 Hz, 3H),2.03-1.94 (m, 1H), 1.38 (s, 4.5H), 1.22 (s, 4.5H); LCMS (electrospray)m/z 425.2 (M + H)+. B  37

¹H NMR (400 MHz, DMSO-d₆) δ 9.57 (d, J = 1.1 Hz, 1H), 7.99-7.91 (m, 1H),7.80 (dd, J = 9.1, 1.9 Hz, 1H), 7.44- 7.35 (m, 1H), 7.34-7.26 (m, 1H),7.23 (d, J = 7.7 Hz, 1H), 2.37 (s, 3H), 2.35 (s, 6H), 2.20 (d, J = 2.7Hz, 3H); LCMS (electrospray) m/z 368.10 (M + H)+. E  38

¹H NMR (400 MHz, DMSO-d₆) δ 9.91 (s, 1H), 8.01-7.84 (m, 2H), 7.66-7.55(m, 2H), 7.47 (d, J = 9.9 Hz, 1H), 6.72 (s, 2H), 5.33-5.05 (m, 1H), 2.58(d, J = 8.2 Hz, 3H), 2.53 (s, 3H), 1.96-1.80 (m, 1H), 1.16-1.05 (m, 1H);LCMS (electrospray) m/z 352.10 (M + H)+. B  39

¹H NMR (400 MHz, DMSO-d₆) δ 9.79 (s, 1H), 7.79 (dd, J = 9.1, 1.9 Hz,1H), 7.53 (d, J = 8.2 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 7.06 (d, J =8.8 Hz, 2H), 6.61 (s, 2H), 5.31-5.04 (m, 1H), 3.76 (t, J = 4.9 Hz, 4H),3.17 (t, J = 4.7 Hz, 4H), 2.65- 2.53 (m, 1H), 1.95-1.80 (m, 1H), 1.15-1.05 (m, 1H); LCMS (electrospray) m/z 381.10 (M + H)+. B  40

¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (s, 1H), 9.53 (s, 1H), 8.11 (s, 1H),7.59 (dd, J = 8.8, 1.6 Hz, 1H), 7.50 (t, J = 3.0 Hz, 1H), 7.44 (d, J =8.8 Hz, 1H), 6.65 (s, 2H), 6.58 (q, J = 1.8 Hz, 1H), 5.30- 5.05 (m, 1H),2.65-2.53 (m, 1H), 2.47 (s, 3H), 1.91-1.77 (m, 1H), 1.16-1.04 (m, 1H);LCMS (electrospray) m/z 350.10 (M + H)+. L  41

¹H NMR (400 MHz, DMSO-d₆) δ 12.18 (s, 1H), 9.66 (s, 1H), 8.29 (s, 1H),7.73- 7.60 (m, 2H), 7.47 (d, J = 9.3 Hz, 1H), 6.70 (s, 2H), 6.58 (q, J =1.8 Hz, 1H), 5.32-5.02 (m, 1H), 2.65-2.54 (m, 1H), 1.92-1.74 (m, 1H),1.18-1.03 (m, 1H); LCMS (electrospray) m/z 370.10 (M + H)+. L  42

¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H), 7.51 (dd, J = 9.1, 1.9 Hz,1H), 7.40- 7.38 (m, 1H), 7.31-7.26 (m, 1H), 7.19 (t, J = 9.1 Hz, 1H),7.11 (d, J = 7.7 Hz, 1H), 6.65 (s, 2H), 5.04- 4.87 (m, 1H), 3.06-2.97(m, 1H), 2.12 (d, J = 2.7 Hz, 3H), 1.60-1.53 (m, 1H), 1.33-1.28 (m, 1H);LCMS (electrospray) m/z 328.10 (M + H)+. B  43

¹H NMR (400 MHz, DMSO-d₆) δ 9.42 (s, 1H), 7.51 (dd, J = 9.1, 1.9 Hz,1H), 7.40- 7.38 (m, 1H), 7.31-7.26 (m, 1H), 7.19 (t, J = 9.1 Hz, 1H),7.11 (d, J = 7.7 Hz, 1H), 6.65 (s, 2H), 5.04-4.87 (m, 1H), 3.06-2.97 (m,1H), 2.12 (d, J = 2.7 Hz, 3H), 1.60-1.53 (m, 1H), 1.33-1.28 (m, 1H);LCMS (electrospray) m/z 328.10 (M + H)+. B  44

¹H NMR (400 MHz, DMSO-d₆) δ 9.62 (s, 1H), 7.58 (dd, J = 9.1, 1.9 Hz,1H), 7.48- 7.41 (m, 4H), 7.37-7.34 (m, 1H), 6.69 (s, 2H), 5.24-5.04 (m,1H), 2.57-2.51 (m, 2H), 1.85-1.77 (m, 1H), 1.10-1.04 (m, 1H); LCMS(electrospray) m/z 348.05 (M + H)+. B  45

¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H), 7.66-7.64 (m, 1H), 7.59 (s,1H), 7.56-7.53 (m, 2H), 7.40 (d, J = 8.0 Hz, 1H), 6.65 (s, 2H),5.23-5.03 (m, 1H), 2.56-2.51 (m, 1H), 2.30 (d, J = 6.6 Hz, 3H),1.86-1.75 (m, 1H), 1.11-1.02 (m, 1H); LCMS (electrospray) m/z 378.10(M + H)+. B  46

¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (br s, 1H), 7.56 (dd, J = 9.0, 1.8 Hz,1H), 7.43 (d, J = 8.8 Hz, 1H), 7.37-7.32 (m, 1H), 7.27-7.22 (m, 1H),7.17 (d, J = 7.6 Hz, 1H), 6.57 (br s, 2H), 3.76-3.72 (m, 1H), 3.01-2.80(m, 4H), 2.17 (d, J = 2.0 Hz, 3H); LCMS (electrospray) m/z 360.1 (M +H)+. B  47

¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (br s, 1H), 7.59 (dd, J = 1.6, 8.8 Hz,1H), 7.47-7.44 (m, 1H), 7.36-7.31 (m, 1H), 7.26-7.21 (m, 1H), 7.17 (d, J= 7.2 Hz, 1H), 6.62 (br s, 2H), 3.75-3.67 (m, 1H), 2.17-2.10 (m, 4H),1.94-1.85 (m, 1H); LCMS (electrospray) m/z 346.10 (M + H)+. B  48

¹H NMR (400 MHz, DMSO-d₆) δ 9.58 (br s, 1H), 7.54 (dd, J = 1.8, 9.0 Hz,1H), 7.42-7.39 (m, 1H), 7.37-7.31 (m, 1H), 7.26-7.22 (m, 1H), 7.17 (d, J= 8.0 Hz, 1H), 6.95 (br s, 2H), 4.67-4.64 (m, 1H), 3.76 (br s, 1H),3.43-3.33 (m, 2H), 2.77-2.66 (m, 1H), 2.17 (d, J = 2.4 Hz, 3H); LCMS(electrospray) m/z 325.10 (M + H)+. B  49

¹H NMR (400 MHz, DMSO-d₆) δ 9.60 (br s, 1H), 7.55 (dd, J = 9.2, 2.0 Hz,1H), 7.42 (d, J = 8.8 Hz, 1H), 7.37-7.31 (m, 1H), 7.24 (t, J = 9.2 Hz,1H), 7.17 (d, J = 8.0 Hz, 1H), 6.49 (s, 2H), 4.11- 3.99 (m, 5H), 2.17(d, J = 2.0 Hz, 3H), 1.37 (s, 9H); LCMS (electrospray) m/z 425.2 (M +H)+. B  50

¹H NMR (400 MHz, DMSO-d₆) δ 9.58 (br s, 1H), 7.52 (dd, J = 9.2, 2.0 Hz,1H), 7.40 (d, J = 8.4 Hz, 1H), 7.37-7.31 (m, 1H), 7.24 (t, J = 8.8 Hz,1H), 7.17 (d, J = 7.6 Hz, 1H), 6.38 (s, 2H), 4.20- 4.13 (m, 1H),3.73-3.67 (m, 4H), 2.17 (d, J = 2.4 Hz, 3H); LCMS (electrospray) m/z325.10 (M + H)+. B  51

¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H), 9.86 (s, 1H), 7.86 (dd, J =9.1, 1.9 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H),7.48-7.39 (m, 2H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H), 6.62 (s, 2H), 6.52(t, J = 1.9 Hz, 1H), 5.36- 5.01 (m, 1H), 2.60 (t, J = 7.1 Hz, 1H),1.96-1.78 (m, 1H), 1.16-1.02 (m, 1H); LCMS (electrospray) m/z 335.10(M + H)+. L  52

¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (s, 1H), 7.79 (dd, J = 9.1, 1.9 Hz,1H), 7.51 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.8 Hz, 1H), 7.05 (d, J =8.8 Hz, 2H), 6.61 (s, 2H), 5.17 (d, J = 67.1 Hz, 1H), 3.25- 3.08 (m,4H), 3.04-2.83 (m, 4H), 2.66- 2.54 (m, 1H), 1.95-1.79 (m, 1H), 1.18-1.02 (m, 1H); LCMS (electrospray) m/z 380.20 (M + H)+. B  53

¹H NMR (400 MHz, DMSO-d₆) δ 9.78 (s, 1H), 7.79 (dd, J = 9.3, 2.2 Hz,1H), 7.50 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.05 (d, J =8.8 Hz, 2H), 6.63 (dd, J = 9.9, 3.3 Hz, 2H), 5.31-5.05 (m, 1H),3.27-3.10 (m, 4H), 2.59 (m, 1H), 2.48- 2.35 (m, 4H), 2.30-2.17 (m, 3H),1.96- 1.79 (m, 1H), 1.18-1.05 (m, 1H); LCMS (electrospray) m/z 394.20(M + H)+. B  54

¹H NMR (400 MHz, DMSO-d₆) δ 9.56 (s, 1H), 7.59-7.53 (m, 3H), 7.35 (dd, J= 13.7, 8.2 Hz, 1H), 7.27-7.18 (m, 3H), 5.28-5.08 (m, 1H), 4.80 (s, 1H),3.07 (d, J = 4.4 Hz, 3H), 2.31 (d, J = 18.7 Hz, 1H), 2.18 (d, J = 2.2Hz, 3H), 1.91- 1.76 (m, 1H), 1.48 (s, 1H), 1.17-1.08 (m, 1H); LCMS(electrospray) m/z 342.10 (M + H)+. F  55

¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (t, J = 1.4 Hz, 1H), 7.70-7.63 (m, 2H),7.35 (dd, J = 13.7, 8.2 Hz, 1H), 7.26 (t, J = 8.5 Hz, 1H), 7.16 (d, J =7.7 Hz, 1H), 5.02 (dd, J = 67.3, 1.9 Hz, 1H), 3.07 (d, J = 12.6 Hz, 6H),2.16 (d, J = 2.2 Hz, 3H), 1.73-1.63 (m, 1H), 1.50 (td, J = 12.9, 6.4 Hz,1H); LCMS (electrospray) m/z 356.10 (M + H)+. G  56

¹H NMR (400 MHz, DMSO-d₆) δ 9.80 (s, 1H), 7.83 (dd, J = 9.1, 1.9 Hz,1H), 7.42 (d, J = 9.3 Hz, 1H), 7.32 (t, J = 8.0 Hz, 1H), 7.13 (s, 1H),7.08-6.92 (m, 2H), 6.65 (s, 2H), 5.35-5.01 (m, 1H), 3.28- 3.13 (m, 4H),2.66-2.53 (m, 1H), 2.49- 2.42 (m, 4H), 2.23 (s, 3H), 1.96-1.79 (m, 1H),1.16-1.04 (m, 1H); LCMS (electrospray) m/z 394.20 (M + H)+. B  57

¹H NMR (400 MHz, DMSO-d₆) δ 11.36 (s, 1H), 9.96 (s, 1H), 7.84 (dd, J =9.1, 1.9 Hz, 1H), 7.58-7.41 (m, 3H), 7.27- 7.11 (m, 2H), 6.75-6.53 (m,3H), 5.35- 4.99 (m, 1H), 2.66-2.55 (m, 1H), 1.94- 1.80 (m, 1H),1.15-1.03 (m, 1H); LCMS (electrospray) m/z 335.10 (M + H)+. L  58

¹H NMR (400 MHz, DMSO-d₆) δ 11.21 (s, 1H), 9.90 (s, 1H), 7.87 (dd, J =9.3, 1.6 Hz, 1H), 7.66 (d, J = 8.2 Hz, 2H), 7.53-7.36 (m, 2H), 7.29 (d,J = 8.2 Hz, 1H), 6.64 (s, 2H), 6.47 (s, 1H), 5.33- 5.04 (m, 1H),2.77-2.55 (m, 1H), 2.00- 1.79 (m, 1H), 1.18-1.02 (m, 1H); LCMS(electrospray) m/z 335.10 (M + H)+. L  59

¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 9.80 (s, 1H), 7.72 (dd, J =9.1, 1.9 Hz, 1H), 7.60 (t, J = 4.4 Hz, 1H), 7.49 (d, J = 9.3 Hz, 1H),7.36 (t, J = 2.7 Hz, 1H), 7.21-7.03 (m, 2H), 6.65 (s, 2H), 6.55 (s, 1H),5.34-5.02 (m, 1H), 2.65-2.54 (m, 1H), 1.93-1.77 (m, 1H), 1.16-1.02 (m,1H); LCMS (electrospray) m/z 335.10 (M + H)+. L  60

¹H NMR (400 MHz, DMSO-d₆) δ 13.21 (s, 1H), 9.62 (s, 1H), 7.78 (s, 1H),7.60 (dd, J = 8.8, 1.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 7.40 (d, J =9.9 Hz, 1H), 6.72 (s, 2H), 5.34-5.00 (m, 1H), 2.64- 2.54 (m, 1H),2.29-2.13 (m, 3H), 1.91- 1.74 (m, 1H), 1.18-1.00 (m, 1H); LCMS(electrospray) m/z 368.10 (M + H)+. L  61

¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 9.57 (s, 1H), 7.73 (s, 1H),7.55 (dd, J = 8.8, 1.6 Hz, 1H), 7.48 (d, J = 8.8 Hz, 1H), 6.70 (s, 2H),5.30-5.03 (m, 1H), 2.95 (d, J = 2.2 Hz, 6H), 2.64-2.53 (m, 1H), 2.17 (s,3H), 1.90-1.75 (m, 1H), 1.17-1.01 (m, 1H); LCMS (electrospray) m/z411.15 (M + H)+. L  62

¹H NMR (400 MHz, DMSO-d₆) δ 13.50 (s, 1H), 9.61 (s, 1H), 7.85 (s, 1H),7.59 (dd, J = 8.8, 1.6 Hz, 1H), 7.51 (d, J = 9.3 Hz, 1H), 6.73 (s, 2H),5.36-4.99 (m, 1H), 2.64-2.54 (m, 1H), 2.52 (s, 3H), 2.22 (d, J = 2.7 Hz,3H), 1.91-1.73 (m, 1H), 1.17-0.99 (m, 1H); LCMS (electrospray) m/z414.10 (M + H)+. L  63

¹H NMR (400 MHz, DMSO-d₆) δ 9.88 (s, 1H), 8.06 (d, J = 2.2 Hz, 1H), 7.93(s, 1H), 7.87 (dd, J = 9.1, 1.9 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 7.58(dd, J = 8.5, 1.9 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.04 (d, J = 2.5Hz, 1H), 6.67 (s, 2H), 5.27-5.10 (m, 1H), 2.61-2.61 (m, 1H), 1.91-1.84(m, 1H), 1.15-1.08 (m, 1H); LCMS (electrospray) m/z 336.10 (M + H)+. L 64

¹H NMR (400 MHz, DMSO-d₆) δ 13.51 (s, 1H), 9.74 (s, 1H), 7.93 (s, 1H),7.68 (dd, J = 9.1, 1.9 Hz, 2H), 7.53 (d, J = 8.8 Hz, 1H), 6.76 (s, 2H),5.16 (d, J = 67.1 Hz, 1H), 2.59 (t, J = 6.6 Hz, 1H), 1.89-1.63 (m, 1H),1.18-0.94 (m, 1H); LCMS (electrospray) m/z 388.05 (M + H)+. L  65

¹H NMR (400 MHz, DMSO-d₆) δ 13.53 (s, 1H), 9.68 (s, 1H), 7.88 (s, 1H),7.64 (d, J = 8.8 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H), 6.73 (s, 2H),5.37-4.97 (m, 1H), 3.00 (s, 6H), 2.63-2.53 (m, 1H), 1.91- 1.66 (m, 1H),1.16-0.97 (m, 1H); LCMS (electrospray) m/z 431.10 (M + H)+. L  66

¹H NMR (400 MHz, DMSO-d₆) δ 13.82 (s, 1H), 9.73 (s, 1H), 8.01 (s, 1H),7.68 (dd, J = 9.1, 1.9 Hz, 1H), 7.53 (d, J = 9.3 Hz, 1H), 6.77 (s, 2H),5.38-4.97 (m, 1H), 2.65-2.53 (m, 4H), 1.92-1.71 (m, 1H), 1.18-0.99 (m,1H); LCMS (electrospray) m/z 434.10 (M + H)+. L  67

¹H NMR (400 MHz, DMSO-d₆) δ 11.23 (s, 1H), 10.15 (s, 1H), 8.78 (d, J =3.3 Hz, 1H), 8.21-8.04 (m, 2H), 7.93 (d, J = 9.3 Hz, 1H), 7.82 (s, 1H),7.69 (s, 3H), 7.53 (d, J = 8.2 Hz, 1H), 7.48-7.24 (m, 3H), 6.53 (s, 1H);LCMS (electrospray) m/z 354.10 (M + H)+. L  68

¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 10.11 (s, 1H), 8.78 (d, J =3.3 Hz, 1H), 8.50 (s, 1H), 8.22 (s, 1H), 8.13 (s, 2H), 7.96 (d, J = 8.8Hz, 1H), 7.87- 7.62 (m, 3H), 7.62-7.34 (m, 2H), 6.55 (s, 1H); LCMS(electrospray) m/z 355.10 (M + H)+. L  69

¹H NMR (400 MHz, DMSO-d₆) δ 12.14 (s, 1H), 9.79 (s, 1H), 8.38 (d, J =9.9 Hz, 1H), 7.76 (d, J = 9.3 Hz, 1H), 7.59 (d, J = 2.2 Hz, 1H), 7.49(d, J = 9.9 Hz, 1H), 6.70 (s, 2H), 6.62 (d, J = 1.6 Hz, 1H), 5.39-4.99(m, 1H), 2.66-2.54 (m, 1H), 1.96-1.75 (m, 1H), 1.19-1.01 (m, 1H); LCMS(electrospray) m/z 354.10 (M + H)+. L  70

¹H NMR (400 MHz, DMSO-d₆) δ 9.85 (s, 1H), 9.47 (d, J = 1.2 Hz, 1H), 7.80(d, J = 9.2 Hz, 1H), 7.68 (dd, J = 9.6, 2.0 Hz, 1H), 7.38-7.33 (m, 1H),7.27 (t, J = 8.8 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 5.06- 4.83 (m, 1H),2.91-2.83 (m, 1H), 2.17 (d, J = 2.0 Hz, 3H), 1.91-1.80 (m, 1H), 1.46 (s,9H), 1.28-1.21 (m, 1H); LCMS (electrospray) m/z 428.20 (M + H)+. H  71

¹H NMR (400 MHz, DMSO-d₆) δ 9.64- 9.51 (m, 1H), 8.44 (br s, 1H), 7.64-7.55 (m, 2H), 7.42-7.30 (m, 1H), 7.29- 7.22 (m, 1H), 7.17 (d, J = 7.2Hz, 1H), 5.37-4.94 (m, 1H), 4.05-3.73 (m, 2H), 2.19 (br s, 1H), 2.16 (d,J = 2.3 Hz, 3H), 2.08 (s, 2H), 2.04-1.96 (m, 2H), 1.92 (br dd, J = 3.4,6.3 Hz, 1H), 1.87-1.79 (m, 2H), 1.30-1.11 (m, 1H); LCMS (electrospray)m/z 382.00 (M + H)+. I  72

¹H NMR (400 MHz, DMSO-d₆) δ 9.93 (br s, 1H), 7.81 (dd, J = 1.9, 9.1 Hz,1H), 7.60 (s, 1H), 7.47 (dd, J = 0.8, 9.2 Hz, 1H), 6.81 (s, 2H),5.32-5.05 (m, 1H), 2.64-2.55 (m, 1H), 2.46 (s, 3H), 1.95- 1.83 (m, 1H),1.19-1.08 (m, 1H); LCMS (electrospray) m/z 317.20 (M + H)+. D  73

¹H NMR (400 MHz, DMSO-d₆) δ 11.56 (s, 1H), 9.63 (s, 1H), 7.65-7.42 (m,4H), 7.19 (d, J = 8.0 Hz, 1H), 6.65 (s, 2H), 6.55 (s, 1H), 5.31-5.05 (m,1H), 2.61-2.54 (m, 1H), 1.88-1.80 (m, 1H), 1.14-1.07 (m, 1H); LCMS(electrospray) m/z 369.10 (M + H)+. L  74

¹H NMR (400 MHz, DMSO-d₆) δ 11.69 (d, J = 18.7 Hz, 1H), 10.08-9.49 (m,1H), 8.86-8.69 (m, 1H), 8.24-7.99 (m, 3H), 7.80-7.57 (m, 4H), 7.55-7.47(m, 1H), 7.47-7.36 (m, 1H), 6.69-6.51 (m, 1H), 2.50 (d, J = 1.6 Hz, 3H);LCMS (electrospray) m/z 369.10 (M + H)+. L  75

¹H NMR (400 MHz, DMSO-d₆) δ 12.20 (s, 1H), 10.10-9.73 (s, 1H), 8.85-8.69(m, 1H), 8.31 (s, 1H), 8.22-8.01 (m, 2H), 7.96-7.60 (m, 5H), 7.56-7.37(m, 1H), 6.59 (t, J = 1.6 Hz, 1H); LCMS (electrospray) m/z 389.10 (M +H)+. L  76

¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (br s, 1H), 9.05-9.02 (m, 2H),7.73-7.69 (m, 1H), 7.63 (d, J = 8.8 Hz, 1H), 7.47 (d, J = 8.8 Hz, 1H),7.34 (q, J = 7.27 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.20- 7.15 (m, 1H),6.56 (s, 2H), 2.17 (s, 3H); LCMS (electrospray) m/z 348.10 (M + H)+. B 77

¹H NMR (400 MHz, DMSO-d₆) δ 9.77 (br s, 1H), 9.44 (s, 1H), 9.16-9.10 (m,1H), 8.05-8.00 (m, 1H), 7.70-7.64 (m, 1H), 7.62 (s, 2H), 7.49-7.44 (m,1H), 7.40-7.31 (m, 1H), 7.25 (t, J = 8.8 Hz, 1H), 7.21-7.16 (m, 1H),2.19 (s, 3H); LCMS (electrospray) m/z 348.10 (M + H)+. L  78

¹H NMR (400 MHz, DMSO-d₆) δ 11.89 (s, 1H), 10.17 (br s, 1H), 9.45 (s,1H), 9.15 (d, J = 4.8 Hz, 1H), 8.49 (s, 1H), 8.22 (s, 1H), 8.07-7.99 (m,2H), 7.60- 7.48 (m, 4H), 6.55-6.54 (m, 1H); LCMS (electrospray) m/z356.10 (M + H)+. L  79

¹H NMR (400 MHz, DMSO-d₆) δ 11.80 (s, 1H), 9.92 (br s, 1H), 9.10-9.02(m, 2H), 8.45 (s, 1H), 8.19 (s, 1H), 7.97 (d, J = 8.8 Hz, 1H), 7.75-7.69(m, 1H), 7.57-7.47 (m, 2H), 6.66-6.41 (m, 3H); LCMS (electrospray) m/z356.10 (M + H)+. L  80

¹H NMR (400 MHz, DMSO-d₆) δ 13.18 (s, 1H), 10.20-9.66 (s, 1H), 8.16 (s,1H), 8.04 (s, 1H), 7.88 (d, J = 9.3 Hz, 1H), 7.66 (d, J = 3.8 Hz, 2H),7.46 (d, J = 9.3 Hz, 1H), 6.66 (s, 2H), 5.40-4.99 (m, 1H), 2.89-2.56 (m,2H), 1.97-1.77 (m, 1H), 1.20-0.97 (m, 1H); LCMS (electrospray) m/z336.10 (M + H)+. L  81

¹H NMR (400 MHz, DMSO-d₆) δ 13.54 (s, 1H), 9.66 (s, 1H), 8.20 (s, 1H),7.75- 7.56 (m, 2H), 7.47 (q, J = 4.6 Hz, 2H), 6.70 (s, 2H), 5.42-4.94(m, 1H), 2.65- 2.53 (m, 1H), 1.92-1.68 (m, 1H), 1.16- 0.98 (m, 1H); LCMS(electrospray) m/z 370.05 (M + H)+. L  82

¹H NMR (400 MHz, DMSO-d₆) δ 11.71 (s, 1H), 9.62 (s, 1H), 8.11 (s, 1H),7.57 (d, J = 8.2 Hz, 1H), 7.50 (s, 1H), 7.41 (d, J = 9.3 Hz, 1H), 6.58(s, 1H), 6.38 (s, 2H), 4.18 (t, J = 7.4 Hz, 1H), 3.74 (d, J = 6.6 Hz,4H), 2.47 (s, 3H); LCMS (electrospray) m/z 347.10 (M + H)+. L  83

¹H NMR (400 MHz, DMSO-d₆) δ 12.17 (s, 1H), 9.74 (s, 1H), 8.72 (s, 2H),8.25 (s, 1H), 7.69-7.67 (m, 2H), 7.47 (d, J = 9.3 Hz, 1H), 6.55 (s, 2H),4.32-4.30 (m, 1H), 4.26-4.21 (m, 2H), 4.13-4.09 (m, 2H); LCMS(electrospray) m/z 367.10 (M + H)+. L  84

¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (s, 1H), 9.72 (s, 1H), 9.41 (s, 1H),9.09 (d, J = 5.5 Hz, 1H), 8.09 (s, 1H), 7.98 (s, 1H), 7.68 (d, J = 8.8Hz, 1H), 7.55 (s, 2H), 7.45 (t, J = 8.5 Hz, 2H), 6.56 (s, 1H); LCMS(electrospray) m/z 370.10 (M + H)+. L  85

¹H NMR (400 MHz, DMSO-d₆) δ 11.72 (s, 1H), 9.67 (br s, 1H), 9.03 (d, J =4.8 Hz, 2H), 8.10 (s, 1H), 7.72-7.67 (m, 2H), 7.51-7.47 (m, 2H),6.62-6.37 (m, 3H); LCMS (electrospray) m/z 370.10 (M + H)+. L  86

¹H NMR (400 MHz, DMSO-d₆) δ 11.82 (s, 1H), 9.95 (br s, 1H), 8.81 (s,2H), 8.51-8.48 (m, 1H), 8.23-8.20 (m, 1H), 7.97-7.93 (m, 1H), 7.61-7.48(m, 2H), 6.61-6.52 (m, 3H), 4.41-3.98 (m, 5H); LCMS (electrospray) m/z333.10 (M + H)+. L  87

¹H NMR (400 MHz, DMSO-d₆) δ 9.50- (br s, 1H), 7.57-7.51 (m, 2H),7.36-7.31 (m, 1H), 7.26-7.17 (m, 2H), 5.27-5.07 (m, 1H), 3.58 (q, 6.0Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.63-2.52 (m, 1H), 2.33 (s, 3H), 2.17(d, J = 1.6 Hz, 3H), 1.89- 1.79 (m, 1H), 1.24-1.10 (m, 1H); LCMS(electrospray) m/z 385.15 (M + H)+. J  88

¹H NMR (400 MHz, DMSO-d₆) δ 10.56 (s, 1H), 9.51 (d, J = 1.1 Hz, 1H),7.83 (d, J = 8.8 Hz, 1H), 7.70 (dd, J = 9.3, 1.6 Hz, 1H), 7.43-7.32 (m,1H), 7.28 (t, J = 9.1 Hz, 1H), 7.21 (d, J = 7.7 Hz, 1H), 5.12-4.82 (m,1H), 2.87-2.73 (m, 1H), 2.18 (d, J = 2.2 Hz, 3H), 2.16 (s, 3H),1.92-1.75 (m, 1H), 1.30-1.13 (m, 1H); LCMS (electrospray) m/z 370.10(M + H)+. K  89

¹H NMR (400 MHz, DMSO-d₆) δ 11.15 (s, 1H), 9.47 (s, 1H), 7.50 (dd, J =9.1, 1.9 Hz, 1H), 7.41-7.32 (m, 2H), 7.28 (d, J = 8.2 Hz, 1H), 6.98 (d,J = 8.2 Hz, 1H), 6.53 (d, J = 33.0 Hz, 3H), 5.30- 4.98 (m, 1H),2.60-2.49 (m, 1H), 2.38 (s, 3H), 1.90-1.68 (m, 1H), 1.11-0.96 (m, 1H);LCMS (electrospray) m/z 349.10 (M + H)+. L  90

¹H NMR (400 MHz, DMSO-d₆) δ 13.13 (s, 1H), 9.54 (br s, 1H), 8.21 (s,1H), 7.56 (dd, J = 9.0, 1.8 Hz, 1H), 7.44 (t, J = 8.8 Hz, 2H), 7.28 (d,J = 8.8 Hz, 1H), 6.65 (s, 2H), 5.27-5.07 (m, 1H), 2.60- 2.54 (m, 1H),1.87-1.78 (m, 1H), 1.17- 1.05 (m, 1H); LCMS (electrospray) m/z 350.10(M + H)+. L  91

¹H NMR (400 MHz, DMSO-d₆) δ 11.75 (s, 1H), 9.88 (br s, 1H), 8.43 (d, J =2.4 Hz, 1H), 8.15 (d, J = 2.4 Hz, 1H), 7.87 (dd, J = 9.0, 2.2 Hz, 1H),7.51 (t, J = 3.2 Hz, 1H), 7.44 (d, J = 9.6 Hz, 1H), 6.61 (s, 2H),6.50-6.49 (m, 1H), 3.85-3.77 (m, 1H), 3.40-3.32 (m, 1H), 3.25-3.20 (m,1H), 3.12-3.05 (m, 2H), 2.60-2.54 (m, 1H), 2.25-1.96 (m, 2H); LCMS(electrospray) m/z 347.10 (M + H)+. L  92

¹H NMR (400 MHz, DMSO-d₆) δ 11.24 (s, 1H), 9.70 (s, 1H), 7.95-7.78 (m,2H), 7.51 (q, J = 4.2 Hz, 1H), 7.46-7.30 (m, 2H), 6.80 (s, 2H), 6.52 (d,J = 2.2 Hz, 1H), 5.34-5.05 (m, 1H), 2.70-2.56 (m, 1H), 1.96-1.81 (m,1H), 1.27-1.04 (m, 1H); LCMS (electrospray) m/z 353.10 (M + H)+. M  93

¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (br s, 1H), 7.58-7.50 (m, 2H), 7.34 (q,J = 7.2 Hz, 1H), 7.24 (t, J = 8.8 Hz, 1H), 7.18 (d, J = 7.6 Hz, 1H),5.30-5.08 (m, 1H), 3.50 (q, 6.6 Hz, 2H), 2.81 (t, J = 6.6 Hz, 2H),2.65-2.52 (m, 1H), 2.17 (d, J = 2.0 Hz, 3H), 1.90-1.79 (m, 1H),1.17-1.08 (m, 1H); LCMS (electrospray) m/z 371.10 (M + H)+. J  94

¹H NMR (400 MHz, DMSO-d₆) δ 11.70 (s, 1H), 9.60 (br s, 1H), 8.09 (s,1H), 7.56 (dd, J = 9.0, 1.8 Hz, 1H), 7.51- 7.47 (m, 1H), 7.44-7.38 (m,1H), 6.57 (d, J = 2.8 Hz, 1H), 6.51 (s, 2H), 3.60- 3.53 (m, 1H),3.10-3.05 (m, 1H), 2.89- 2.74 (m, 3H), 2.46 (s, 3H), 2.03-1.88 (m, 2H);LCMS (electrospray) m/z 361.10 (M + H)+. L  95

¹H NMR (400 MHz, DMSO-d₆) δ 12.18 (s, 1H), 9.72 (br s, 1H), 8.27 (s,1H), 7.67 (d, J = 3.2 Hz, 1H), 7.63 (dd, J = 9.0, 2.2 Hz, 1H), 7.47-7.41(m, 1H), 6.67-6.51 (m, 3H), 3.60-3.53 (m, 1H), 3.10-3.05 (m, 1H),2.90-2.74 (m, 3H), 2.01-1.88 (m, 2H); LCMS (electrospray) m/z 381.10(M + H)+. L  96

¹H NMR (400 MHz, DMSO-d₆) δ 11.40 (s, 1H), 9.82 (s, 1H), 7.79 (dd, J =11.5, 1.6 Hz, 1H), 7.57-7.40 (m, 2H), 7.29- 7.12 (m, 2H), 6.84 (s, 2H),6.64 (s, 1H), 5.34-5.02 (m, 1H), 2.74-2.55 (m, 1H), 1.96-1.80 (m, 1H),1.22-1.06 (m, 1H); LCMS (electrospray) m/z 353.10 (M + H)+. M  97

¹H NMR (400 MHz, DMSO-d₆) δ 11.73 (s, 1H), 9.35 (s, 1H), 8.11 (s, 1H),7.64 (dd, J = 11.3, 1.4 Hz, 1H), 7.50 (t, J = 3.0 Hz, 1H), 6.84 (s, 2H),6.58 (s, 1H), 5.37-5.03 (m, 1H), 2.74-2.56 (m, 1H), 2.48 (d, J = 4.9 Hz,3H), 1.96-1.75 (m, 1H), 1.23-1.02 (m, 1H); LCMS (electrospray) m/z368.10 (M + H)+. M  98

¹H NMR (400 MHz, DMSO-d₆) δ 9.99 (s, 1H), 8.19 (d, J = 7.7 Hz, 1H), 8.04(s, 1H), 7.95-7.83 (m, 2H), 7.54-7.36 (m, 3H), 6.68 (s, 2H), 5.33-5.04(m, 1H), 2.65-2.55 (m, 1H), 1.97-1.79 (m, 1H), 1.66 (s, 9H), 1.16-1.05(m, 1H); LCMS (electrospray) m/z 435.15 (M + H)+. L  99

¹H NMR (400 MHz, DMSO-d₆) δ 9.35 (s, 1H), 7.62-7.59 (m, 1H), 7.36-7.19(m, 3H), 6.87 (s, 1H), 5.29-5.10 (m, 1H), 2.61-2.52 (m, 1H), 2.19 (s,3H), 1.89- 1.84 (m, 1H), 1.17-1.13 (m, 1H); LCMS (electrospray) m/z346.10 (M + H)+. M 100

¹H NMR (400 MHz, DMSO-d₆) δ 11.14 (s, 1H), 9.55 (s, 1H), 7.53 (dd, J =8.8, 1.6 Hz, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.35 (d, J = 8.2 Hz, 1H),7.30 (t, J = 2.7 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.63 (s, 2H), 6.07(s, 1H), 5.33-5.00 (m, 1H), 2.65-2.51 (m, 1H), 2.26 (s, 3H), 1.90- 1.73(m, 1H), 1.14-0.98 (m, 1H); LCMS (electrospray) m/z 349.10 (M + H)+. L101

¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 9.83 (s, 1H), 7.72 (dt, J =8.8, 1.6 Hz, 1H), 7.57-7.40 (m, 3H), 7.08 (dd, J = 11.0, 8.8 Hz, 1H),6.68 (s, 2H), 6.44 (t, J = 2.2 Hz, 1H), 5.32-5.03 (m, 1H), 2.65-2.53 (m,1H), 1.94-1.74 (m, 1H), 1.15-1.02 (m, 1H); LCMS (electrospray) m/z353.10 (M + H)+. L 102

¹H NMR (400 MHz, DMSO-d₆) δ 12.54 (s, 1H), 9.88 (br s, 1H), 8.28 (s,1H), 7.93-7.62 (m, 3H), 7.52-7.42 (m, 2H), 6.65 (s, 2H), 5.29-5.07 (m,1H), 2.64- 2.56 (m, 1H), 1.93-1.82 (m, 1H), 1.17- 1.07 (m, 1H); LCMS(electrospray) m/z 336.10 (M + H)+. L 103

¹H NMR (400 MHz, DMSO-d₆) δ 12.65 (s, 0.5H), 12.50 (s, 0.5H), 9.54 (brs, 1H), 8.29 (s, 0.5H), 8.24 (s, 0.5H), 7.59-7.40 (m, 3H), 7.14 (t, J =9.0 Hz, 1H), 6.65 (s, 2H), 5.28-5.05 (m, 1H), 2.62-2.53 (m, 1H), 2.52(s, 1.5H), 2.44 (s, 1.5H), 1.89-1.77 (m, 1H), 1.14-1.04 (m, 1H); LCMS(electrospray) m/z 350.10 (M + H)+. L 104

¹H NMR (400 MHz, DMSO-d₆) δ 11.86 (s, 1H), 10.10 (br s, 1H), 8.27 (d, J= 4.8 Hz, 1H), 7.91 (dd, J = 9.2, 2.0 Hz, 1H), 7.59 (t, J = 3.0 Hz, 1H),7.49 (d, J = 9.6 Hz, 1H), 7.25 (d, J = 4.8 Hz, 1H), 6.72 (s, 2H),6.68-6.65 (m, 1H), 5.26- 5.03 (m, 1H), 2.61-2.52 (m, 1H), 1.91- 1.79 (m,1H), 1.12-1.05 (m, 1H); LCMS (electrospray) m/z 336.10 (M + H)+. L 105

¹H NMR (400 MHz, DMSO-d₆) δ 11.49 (s, 1H), 10.02 (s, 1H), 7.97-7.77 (m,3H), 7.56-7.37 (m, 2H), 7.25-7.12 (m, 2H), 6.58 (s, 2H), 5.34-5.04 (m,1H), 2.71-2.54 (m, 1H), 1.97-1.81 (m, 1H), 1.17-1.02 (m, 1H); LCMS(electrospray) m/z 335.10 (M + H)+. L 106

¹H NMR (400 MHz, DMSO-d₆) δ 9.54 (br s, 1H), 8.15 (s, 1H), 7.61-7.52 (m,2H), 7.44 (d, J = 8.8 Hz, 1H), 6.67 (br s, 2H), 6.60 (d, J = 3.2 Hz,1H), 5.28- 5.06 (m, 1H), 3.84 (s, 3H), 2.63-2.53 (m, 1H), 2.46 (s, 3H),1.89-1.77 (m, 1H), 1.14-1.04 (m, 1H); LCMS (electrospray) m/z 364.10(M + H)+. L 107

¹H NMR (400 MHz, DMSO-d₆) δ 8.49 (s, 1H), 7.35-7.25 (m, 3H), 7.21 (t, J= 9.0 Hz, 1H), 7.14 (d, J = 7.2 Hz, 1H), 5.71 (s, 2H), 2.94 (s, 3H),2.91-2.84 (m, 1H), 2.16 (s, 3H), 0.60-0.51 (m, 4H); LCMS (electrospray)m/z 339.10 (M + H)+. N 108

¹H NMR (400 MHz, DMSO-d₆) δ 9.16 (t, J = 1.4 Hz, 1H), 7.40-7.29 (m, 4H),7.25-7.20 (m, 1H), 7.17 (d, J = 7.6 Hz, 1H), 6.03 (s, 2H), 4.84-4.64 (m,1H), 2.82-2.75 (m, 1H), 2.17 (d, J = 1.4 Hz, 3H), 1.19-1.04 (m, 4H);LCMS (electrospray) m/z 343.10 (M + H)+. N 109

¹H NMR (400 MHz, DMSO-d₆) δ 9.20 (t, J = 1.4 Hz, 1H), 7.38-7.30 (m, 3H),7.28-7.20 (m, 2H), 7.17 (d, J = 7.6 Hz, 1H), 5.98 (s, 2H), 2.80-2.74 (m,1H), 2.17 (d, J = 2.0 Hz, 3H), 0.69-0.55 (m, 4H); LCMS (electrospray)m/z 325.10 (M + H)+. N 110

¹H NMR (400 MHz, DMSO-d₆) δ 12.04 (s, 1H), 10.02 (s, 1H), 8.31 (t, J =2.5 Hz, 1H), 8.23 (d, J = 7.1 Hz, 1H), 8.00 (d, J = 2.2 Hz, 1H), 7.91(dd, J = 9.1, 1.9 Hz, 1H), 7.49-7.43 (m, 1H), 7.24 (q, J = 4.2 Hz, 1H),6.61 (s, 2H), 5.27-5.08 (m, 1H), 2.59-2.59 (m, 1H), 1.93-1.87 (m, 1H),1.14-1.08 (m, 1H); LCMS (electrospray) m/z 336.10 (M + H)+. L 111

¹H NMR (400 MHz, DMSO-d₆) δ 11.66 (s, 1H), 9.88 (s, 1H), 7.86 (d, J =2.2 Hz, 1H), 7.82 (dd, J = 9.1, 1.9 Hz, 1H), 7.77 (d, J = 1.6 Hz, 1H),7.46 (d, J = 8.8 Hz, 1H), 7.41 (d, J = 9.3 Hz, 1H), 7.17 (dd, J = 8.4,2.1 Hz, 1H), 6.58 (s, 2H), 5.23-5.08 (m, 1H), 2.56-2.56 (m, 1H),1.89-1.84 (m, 1H), 1.12-1.05 (m, 1H); LCMS (electrospray) m/z 369.10(M + H)+. L 112

¹H NMR (400 MHz, DMSO-d₆) δ 9.82 (s, 1H), 9.10 (s, 1H), 9.06 (t, J = 1.4Hz, 1H), 7.39 (d, J = 1.1 Hz, 2H), 7.33-7.16 (m, 3H), 6.18 (s, 2H), 2.16(d, J = 2.2 Hz, 3H), 1.90 (s, 3H); LCMS (electrospray) m/z 342.10 (M +H)+. O 113

¹H NMR (400 MHz, DMSO-d₆) δ 11.42 (s, 1H), 9.96 (s, 1H), 7.86 (dd, J =9.1, 1.9 Hz, 1H), 7.49 (d, J = 8.8 Hz, 1H), 7.45 (dd, J = 6.0, 3.8 Hz,1H), 7.21 (dd, J = 9.6, 1.4 Hz, 1H), 7.04 (dd, J = 10.4, 2.2 Hz, 1H),6.80 (s, 2H), 6.58 (s, 1H), 5.22-5.05 (m, 1H), 2.58-2.55 (m, 1H),1.87-1.81 (m, 1H), 1.10-1.06 (m, 1H); LCMS (electrospray) m/z 353.10(M + H)+. L 114

¹H NMR (400 MHz, DMSO-d₆) δ 11.25 (s, 1H), 9.60 (s, 1H), 7.63 (dd, J =8.8, 1.6 Hz, 1H), 7.55 (d, J = 9.3 Hz, 1H), 7.32 (t, J = 2.7 Hz, 1H),7.25 (d, J = 10.4 Hz, 1H), 6.96 (s, 2H), 6.09 (t, J = 2.2 Hz, 1H),5.27-5.07 (m, 1H), 2.62- 2.55 (m, 1H), 2.16 (d, J = 2.7 Hz, 3H),1.87-1.79 (m, 1H), 1.16-1.09 (m, 1H); LCMS (electrospray) m/z 367.10(M + H)+. L 115

¹H NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.94 (d, J = 4.4 Hz, 1H), 8.10(d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.8 Hz, 1H), 7.82-7.78 (m, 1H), 7.68(d, J = 8.8 Hz, 1H), 7.61 (t, J = 7.7 Hz, 1H), 7.55-7.50 (m, 2H), 6.75(s, 2H), 5.21-5.05 (m, 1H), 2.58-2.52 (m, 1H), 1.82-1.76 (m, 1H),1.11-1.02 (m, 1H); LCMS (electrospray) m/z 347.10 (M + H)+. L 116

¹H NMR (400 MHz, DMSO-d₆) δ 9.86- 10.14 (1H), 9.19 (d, J = 2.2 Hz, 1H),8.64 (d, J = 2.2 Hz, 1H), 8.08-8.00 (m, 3H), 7.78-7.74 (m, 1H), 7.64 (t,J = 7.1 Hz, 1H), 7.52 (d, J = 9.3 Hz, 1H), 6.74 (s, 2H), 5.25-5.09 (m,1H), 2.54-2.63 (m, 1H), 1.88-1.82 (m, 1H), 1.15-1.08 (m, 1H); LCMS(electrospray) m/z 347.10 (M + H)+. L 117

¹H NMR (400 MHz, DMSO-d₆) δ 9.67 (s, 1H), 9.37 (s, 1H), 8.49 (s, 1H),8.23 (d, J = 7.7 Hz, 1H), 7.85 (d, J = 8.2 Hz, 1H), 7.82-7.78 (m, 1H),7.73 (td, J = 7.4, 1.1 Hz, 1H), 7.66 (dd, J = 9.1, 1.9 Hz, 1H), 7.50 (d,J = 8.8 Hz, 1H), 6.71 (s, 2H), 5.22-5.04 (m, 1H), 2.58-2.54 (m, 1H),1.83-1.75 (m, 1H), 1.09-1.03 (m, 1H); LCMS (electrospray) m/z 347.10(M + H)+. L 118

¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 7.51 (d, J = 9.1 Hz, 1H), 7.38(d, J = 9.9 Hz, 1H), 7.31-7.24 (m, 4H), 6.63 (s, 2H), 5.22-5.04 (m, 1H),2.55-2.50 (m, 1H), 2.23 (s, 3H), 1.83-1.76 (m, 1H), 1.08-1.03 (m, 1H);LCMS (electrospray) m/z 311.10 (M + H)+. L 119

¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 7.70 (d, J = 9.3 Hz, 1H),7.44-7.36 (m, 3H), 7.17 (d, J = 7.7 Hz, 1H), 7.09 (dd, J = 7.7, 6.6 Hz,1H), 6.67 (s, 2H), 5.08-4.91 (m, 1H), 4.77 (t, J = 3.8 Hz, 1H), 4.65 (t,J = 3.8 Hz, 1H), 4.33 (t, J = 3.8 Hz, 1H), 4.26 (t, J = 3.8 Hz, 1H),3.10-3.02 (m, 1H), 1.66-1.55 (m, 1H), 1.39-1.31 (m, 1H); LCMS(electrospray) m/z 358.10 (M + H)+. L 120

¹H NMR (400 MHz, DMSO-d₆) δ 9.71 (s, 1H), 7.70 (d, J = 9.1 Hz, 1H), 7.42(d, J = 9.3 Hz, 1H), 7.38-7.32 (m, 1H), 7.29- 7.24 (m, 2H), 6.72 (s,2H), 5.09-4.92 (m, 1H), 4.55 (t, J = 3.8 Hz, 1H), 4.43 (t, J = 3.8 Hz,1H), 4.15 (t, J = 3.6 Hz, 1H), 4.08 (t, J = 3.6 Hz, 1H), 3.08-3.03 (m,1H), 1.64-1.59 (m, 1H), 1.38-1.33 (m, 1H); LCMS (electrospray) m/z376.10 (M + H)+. L 121

¹H NMR (400 MHz, DMSO-d₆) δ 9.47 (s, 1H), 7.48 (dd, J = 9.1, 1.9 Hz,1H), 7.38 (q, J = 1.6 Hz, 1H), 7.31 (d, J = 8.8 Hz, 1H), 6.62 (s, 2H),6.32 (q, J = 1.8 Hz, 1H), 6.28 (t, J = 3.6 Hz, 1H), 5.21-5.03 (m, 1H),2.55-2.53 (m, 2H), 1.83-1.77 (m, 1H), 1.28 (s, 9H), 1.08-1.03 (m, 1H);LCMS (electrospray) m/z 385.10 (M + H)+. L 122

¹H NMR (400 MHz, DMSO-d₆) δ 9.70 (s, 1H), 7.82 (d, J = 9.1 Hz, 1H), 7.66(s, 1H), 7.35-7.32 (m, 2H), 6.61-6.60 (m, 3H), 5.22-5.05 (m, 1H),2.57-2.57 (m, 1H), 1.87-1.80 (m, 1H), 1.59 (s, 9H), 1.13-1.05 (m, 1H);LCMS (electrospray) m/z 385.10 (M + H)+. L 123

¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.39(d, J = 8.2 Hz, 1H), 7.32-7.27 (m, 1H), 7.20 (t, J = 8.5 Hz, 1H), 7.09(d, J = 6.6 Hz, 1H), 6.65 (s, 2H), 5.22-5.05 (m, 1H), 4.33 (t, J = 5.2Hz, 1H), 3.23 (q, J = 6.0 Hz, 2H), 2.55-2.50 (m, 3H), 1.82-1.76 (m, 1H),1.55-1.50 (m, 2H), 1.07-1.03 (m, 1H); LCMS (electrospray) m/z 372.10(M + H)+. L 124

¹H NMR (400 MHz, DMSO-d₆) δ 11.45 (s, 1H), 9.76 (s, 1H), 7.76 (dd, J =9.1, 1.9 Hz, 1H), 7.37 (d, J = 9.3 Hz, 1H), 6.85-6.85 (m, 1H), 6.59 (s,2H), 6.43 (s, 1H), 6.13-6.12 (m, 1H), 5.26-5.09 (m, 1H), 2.53-2.62 (m,1H), 1.90-1.90 (m, 1H), 1.10-1.10 (m, 1H); LCMS (electrospray) m/z285.10 (M + H)+. L 125

¹H NMR (400 MHz, DMSO-d₆) δ 11.09 (s, 1H), 9.70 (s, 1H), 7.83 (d, J =9.3 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 7.27 (s, 1H), 6.86 (s, 1H), 6.71(s, 2H), 6.39 (s, 1H), 5.26-5.08 (m, 1H), 2.60-2.56 (m, 1H), 1.91-1.85(m, 1H), 1.14-1.10 (m, 1H); LCMS (electrospray) m/z 285.10 (M + H)+. L126

¹H NMR (400 MHz, DMSO-d₆) δ 9.49 (s, 1H), 7.55 (dd, J = 9.1, 1.9 Hz,1H), 7.43 (d, J = 9.9 Hz, 1H), 7.37-7.32 (m, 1H), 7.25 (t, J = 9.1 Hz,1H), 7.13 (d, J = 6.6 Hz, 1H), 6.69 (s, 2H), 5.25-5.08 (m, 1H), 4.71 (t,J = 5.5 Hz, 1H), 3.50-3.40 (m, 2H), 2.74 (t, J = 7.4 Hz, 2H), 2.59- 2.56(m, 1H), 1.86-1.80 (m, 1H), 1.12- 1.05 (m, 1H); LCMS (electrospray) m/z358.10 (M + H)+. L 127

¹H NMR (400 MHz, DMSO-d₆) δ 9.61 (s, 1H), 7.67 (dd, J = 8.8, 1.6 Hz,1H), 7.48-7.43 (m, 2H), 7.30-7.21 (m, 2H), 6.70 (s, 2H), 5.26-5.06 (m,2H), 4.39 (d, J = 4.4 Hz, 2H), 2.59-2.59 (m, 1H), 1.87-1.81 (m, 1H),1.14-1.07 (m, 1H); LCMS (electrospray) m/z 344.10 (M + H)+. L 128

¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H), 7.48 (dd, J = 9.1, 1.9 Hz,1H), 7.39-7.31 (m, 3H), 7.28-7.20 (m, 2H), 6.62 (s, 2H), 5.22-5.05 (m,1H), 4.56 (t, J = 5.5 Hz, 1H), 3.44 (q, J = 6.6 Hz, 2H), 2.68 (t, J =7.4 Hz, 2H), 2.56-2.52 (m, 1H), 1.82-1.76 (m, 1H), 1.07-1.03 (m, 1H);LCMS (electrospray) m/z 340.10 (M + H)+. L 129

¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H), 7.45 (dd, J = 8.8, 1.6 Hz,1H), 7.38-7.31 (m, 3H), 7.26-7.19 (m, 2H), 6.62 (s, 2H), 5.23-5.02 (m,1H), 4.32 (t, J = 5.2 Hz, 1H), 3.27-3.22 (m, 2H), 2.58-2.50 (m, 3H),1.83-1.75 (m, 1H), 1.57-1.50 (m, 2H), 1.10-1.03 (m, 1H); LCMS(electrospray) m/z 354.10 (M + H)+. L 130

¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 7.50-7.38 (m, 4H), 7.36-7.25(m, 2H), 6.64 (s, 2H), 5.21-5.04 (m, 1H), 4.52 (dt, J = 47.3, 6.6 Hz,2H), 2.93 (dt, J = 23.6, 6.3 Hz, 2H), 2.55-2.50 (m, 1H), 1.82-1.76 (m,1H), 1.08-1.03 (m, 1H); LCMS (electrospray) m/z 342.10 (M + H)+. L 131

¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (s, 1H), 7.52-7.41 (m, 2H), 7.39-7.24(m, 2H), 7.15 (d, J = 6.6 Hz, 1H), 6.69 (s, 2H), 5.25-5.07 (m, 1H), 4.32(dt, J = 47.3, 5.8 Hz, 2H), 2.69-2.65 (m, 2H), 2.59-2.56 (m, 1H),1.86-1.74 (m, 3H), 1.10-1.06 (m, 1H); LCMS (electrospray) m/z 374.10(M + H)+. L 132

¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 7.46 (dd, J = 9.1, 1.9 Hz,1H), 7.39-7.35 (m, 3H), 7.29-7.22 (m, 2H), 6.63 (s, 2H), 5.21-5.04 (m,1H), 4.35 (t, J = 5.8 Hz, 1H), 4.23 (t, J = 6.0 Hz, 1H), 2.63 (t, J =8.0 Hz, 2H), 2.54-2.54 (m, 1H), 1.82-1.72 (m, 3H), 1.06-1.03 (m, 1H);LCMS (electrospray) m/z 356.10 (M + H)+. L 133

¹H NMR (400 MHz, DMSO-d₆) δ 9.40 (s, 1H), 7.41 (dd, J = 9.1, 1.9 Hz,1H), 7.35 (d, J = 9.9 Hz, 1H), 6.62 (s, 2H), 6.44 (dd, J = 11.5, 2.7 Hz,1H), 6.24 (dd, J = 9.3, 2.7 Hz, 1H), 5.34 (s, 2H), 5.21- 5.04 (m, 1H),2.53-2.53 (m, 1H), 1.87 (s, 3H), 1.82-1.76 (m, 1H), 1.07-1.03 (m, 1H);LCMS (electrospray) m/z 343.10 (M + H)+. B 134

¹H NMR (400 MHz, DMSO-d₆) δ 9.64 (s, 1H), 7.57 (d, J = 9.3 Hz, 1H), 7.34(d, J = 8.8 Hz, 1H), 7.07 (d, J = 9.3 Hz, 1H), 6.58 (s, 2H), 6.46 (d, J= 13.2 Hz, 1H), 5.35 (s, 2H), 5.23-5.02 (m, 1H), 2.54- 2.51 (m, 1H),2.04 (s, 3H), 1.85-1.78 (m, 1H), 1.09-1.03 (m, 1H); LCMS (electrospray)m/z 343.10 (M + H)+. B 135

¹H NMR (400 MHz, DMSO-d₆) δ 8.93 (br s, 1H), 7.48-7.43 (m, 1H), 7.42-7.38 (m, 1H), 7.37-7.30 (m, 1H), 7.27- 7.21 (m, 1H), 7.17 (d, J = 7.7Hz, 1H), 6.40 (s, 2H), 3.82 (s, 3H), 2.17 (d, J = 2.3 Hz, 3H); LCMS(electrospray) m/z 300.10 (M + H)+ P 136

¹H NMR (400 MHz, DMSO-d₆) δ 9.46 (s, 1H), 7.47 (dd, J = 8.8, 1.6 Hz,1H), 7.41-7.35 (m, 2H), 7.27 (dd, J = 9.6, 8.0 Hz, 1H), 7.14 (d, J = 7.7Hz, 1H), 6.66 (s, 2H), 5.23-5.02 (m, 1H), 4.47 (dt, J = 47.1, 6.5 Hz,2H), 2.96 (dt, J = 22.0, 6.3 Hz, 2H), 2.55-2.50 (m, 1H), 1.84-1.74 (m,1H), 1.10-1.02 (m, 1H); LCMS (electrospray) m/z 360.10 (M + H)+. L 137

¹H NMR (400 MHz, DMSO-d₆) δ 9.44 (s, 1H), 7.50 (d, J = 8.8 Hz, 1H),7.41-7.36 (m, 3H), 7.33-7.29 (m, 2H), 7.24 (d, J = 7.1 Hz, 1H), 6.62 (s,2H), 5.22-5.05 (m, 1H), 4.06 (d, J = 5.5 Hz, 2H), 2.54-2.52 (m, 1H),1.82-1.77 (m, 1H), 1.30 (s, 9H), 1.20-1.12 (m, 2H), 1.08-1.03 (m, 1H);LCMS (electrospray) m/z 425.20 (M + H)+. L 138

¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H), 7.62 (d, J = 6.6 Hz, 1H), 7.54(dd, J = 8.8, 1.6 Hz, 1H), 7.46 (td, J = 7.6, 1.5 Hz, 1H), 7.41-7.38 (m,2H), 7.32 (d, J = 7.7 Hz, 1H), 6.65 (s, 2H), 6.50 (s, 2H), 5.24-5.03 (m,1H), 3.85 (s, 2H), 2.56-2.53 (m, 1H), 1.83-1.76 (m, 1H), 1.09-1.03 (m,1H); LCMS (electrospray) m/z 326.10 (M + H)+. L 139

¹H NMR (400 MHz, DMSO-d₆) δ 9.49- 9.34 (m, 1H), 7.52-7.48 (m, 1H),7.47-7.43 (m, 2H), 7.42-7.40 (m, 1H), 7.39-7.33 (m, 1H), 7.33-7.25 (m,1H), 6.73-6.60 (m, 2H) 5.10-4.87 (m, 1H), 4.63-4.44 (m, 2H), 3.09-3.01(m, 1H), 3.00-2.90 (m, 2H), 1.66-1.53 (m, 1H), 1.34 (dq, J = 12.73, 6.27Hz, 1H); LCMS (electrospray) m/z 342.10 (M + H)+ L 140

¹H NMR (400 MHz, DMSO-d₆) δ 9.51- 9.33 (m, 1H), 7.53-7.47 (m, 1H), 7.47-7.44 (m, 1H), 7.44-7.42 (m, 1H), 7.41- 7.38 (m, 1H), 7.34 (td, J = 7.32,1.25 Hz, 1H), 7.29-7.25 (m, 1H), 6.75-6.57 (m, 2H), 5.10-4.88 (m, 1H),4.62-4.46 (m, 2H), 3.10-3.01 (m, 1H), 3.01-2.90 (m, 2H), 1.66-1.53 (m,1H), 1.34 (dq, J = 12.65, 6.25 Hz, 1H); LCMS (electrospray) m/z 342.00(M + H)+ L 141

¹H NMR (400 MHz, DMSO-d₆) δ 9.86- 9.69 (m, 1H), 8.48 (s, 1H) 7.70 (dd, J= 9.13, 1.88 Hz, 1H), 7.48-7.18 (m, 5H) 6.68 (br s, 2H) 5.40-4.99 (m,1H), 4.64-4.35 (m, 2H), 4.26-4.03 (m, 2H), 1.96-1.74 (m, 1H), 1.27-0.95(m, 2H); LCMS (electrospray) m/z 376.10 (M + H)+ L 142

¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 7.45 (dd, J = 8.8, 2.2 Hz,1H), 7.34 (d, J = 8.2 Hz, 1H), 6.92 (d, J = 8.2 Hz, 1H), 6.59 (s, 2H),6.49 (dd, J = 8.0, 2.5 Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H), 5.21- 5.02 (m,1H), 4.97 (s, 2H), 2.55-2.51 (m, 1H), 2.05 (s, 3H), 1.83-1.77 (m, 1H),1.08-1.03 (m, 1H); LCMS (electrospray) m/z 325.10 (M + H)+. B 143

¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (s, 1H), 7.42 (d, J = 8.8 Hz, 1H), 7.26(d, J = 8.8 Hz, 1H), 6.98-6.94 (m, 1H), 6.58 (d, J = 7.7 Hz, 3H), 6.49(d, J = 7.7 Hz, 1H), 5.24-5.07 (m, 1H), 4.61 (s, 2H), 2.55-2.53 (m, 1H),1.92 (d, J = 5.5 Hz, 3H), 1.84-1.79 (m, 1H), 1.10-1.05 (m, 1H); LCMS(electrospray) m/z 325.10 (M + H)+. B 144

¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 7.46 (dd, J = 9.1, 1.9 Hz,1H), 7.38 (d, J = 8.5 Hz, 1H), 7.25-7.20 (m, 2H), 7.15-7.13 (m, 1H),7.03 (dd, J = 12.9, 1.4 Hz, 1H), 6.65 (s, 2H), 5.42 (d, J = 13.2 Hz,1H), 5.22-5.02 (m, 1H), 3.46 (s, 3H), 2.53 (q, J = 7.7 Hz, 1H), 1.80 (d,J = 23.6 Hz, 1H), 1.07 (t, J = 6.6 Hz, 1H); LCMS (electrospray) m/z370.10 (M + H)+. B 145

¹H NMR (400 MHz, DMSO-d₆) δ 9.52 (s, 1H), 7.64-7.55 (m, 1H), 7.48-7.39(m, 3H), 7.32 (dd, J = 10.7, 8.0 Hz, 1H), 7.23 (d, J = 6.6 Hz, 1H), 6.70(s, 2H), 6.44 (dd, J = 17.9, 11.8 Hz, 1H), 5.70 (d, J = 17.6 Hz, 1H),5.50 (d, J = 11.5 Hz, 1H), 5.26-5.06 (m, 1H), 2.57 (t, J = 7.7 Hz, 1H),1.88-1.80 (m, 1H), 1.10 (qd, J = 6.3, 2.6 Hz, 1H) LCMS (electrospray)m/z 340.10 (M + H)+. B 146

¹H NMR (400 MHz, DMSO-d₆) δ 9.45 (s, 1H), 7.48-7.36 (m, 2H), 6.66 (s,2H), 6.37-6.27 (m, 2H), 5.57 (d, J = 3.0 Hz, 1H), 5.30-5.05 (m, 1H),2.76 (d, J = 4.4 Hz, 3H), 2.64-2.52 (m, 1H), 1.92 (d, J = 6.6 Hz, 3H),1.90-1.76 (m, 1H), 1.13- 1.04 (m, 1H); LCMS (electrospray) m/z 357.10(M + H)+. B 147

¹H NMR (400 MHz, DMSO-d₆) δ 9.51 (s, 1H), 7.55 (dd, J = 9.1, 1.9 Hz,1H), 7.41 (d, J = 9.9 Hz, 1H), 6.92 (dd, J = 11.3, 2.5 Hz, 1H), 6.82(dd, J = 9.1, 2.5 Hz, 1H), 6.68 (s, 2H), 5.34-5.01 (m, 1H), 2.71 (d, J =14.8 Hz, 6H), 2.64-2.53 (m, 1H), 2.13 (d, J 7.4 Hz, 3H), 1.93-1.75 (m,1H), 1.16-0.99 (m, 1H); LCMS (electrospray) m/z 371.15 (M + H)+. B 148

¹H NMR (400 MHz, DMSO-d₆) δ 9.46- 9.28 (m, 1H), 7.57 (s, 1H) 7.37-7.33(m, 1H) 7.33-7.29 (m, 1H), 7.09-7.02 (m, 1H), 6.74-6.70 (m, 1H),6.68-6.65 (m, 1H), 6.42 (br s, 1H), 5.25-5.01 (m, 1H), 2.12 (d, J = 1.59Hz, 3H), 1.88- 1.75 (m, 1H), 1.14-1.02 (m, 2H); LCMS (electrospray) m/z343.10 (M + H)+ Q 149

¹H NMR (400 MHz, DMSO-d₆) δ 13.52 (br s, 1H) 9.38 (s, 1H) 7.90 (s, 1H)7.43 (m, 2H) 7.27 (br d, J = 2.63 Hz, 1H) 6.03 (s, 2H) 3.00 (br s, 6H)2.77 (m, 1H) 0.62-0.69 (m, 2H) 0.53-0.60 (m, 2H); LCMS (electrospray)m/z 428.10 (M + H)+ L 150

¹H NMR (400 MHz, DMSO-d₆) δ 9.89- 9.54 (m, 1H), 7.70 (dd, J = 9.07, 1.94Hz, 1H), 7.51-7.15 (m, 5H), 6.70 (br s, 2H), 5.16-4.84 (m, 1H),4.63-4.39 (m, 2H), 4.22-4.02 (m, 2H), 3.11-2.95 (m, 2H), 1.84-1.54 (m,1H), 1.36 (dd, J = 12.69, 6.44 Hz, 1H); LCMS (electrospray) m/z 376.10(M + H)+ L 151

¹H NMR (400 MHz, DMSO-d₆) δ 13.82 (s, 1H) 9.15 (s, 1H) 8.08 (s, 1H) 7.64(d, J = 9.11, 1H) 7.53 (d, J = 9.05 Hz, 1H) 6.29-6.56 (m, 2H) 5.01-5.10(m, 1H) 3.80-4.03 (m, 4H) 2.56-2.64 (m, 4H) 1.05 (d, J = 7.09 Hz, 3H);LCMS (electrospray) m/z 476.00 (M + H)+ R 152

¹H NMR (400 MHz, DMSO-d₆) δ 11.41 (s, 1H), 8.60 (d, J = 7.1 Hz, 1H),8.11 (d, J = 1.1 Hz, 1H), 7.50 (q, J = 2.6 Hz, 2H), 7.29-7.21 (m, 3H),6.64 (s, 1H), 6.58 (s, 2H), 2.54-2.52 (m, 1H), 1.00- 0.97 (m, 2H),0.94-0.91 (m, 2H) S 153

¹H NMR (400 MHz, DMSO-d₆) δ 13.23 (s, 1H), 8.66 (d, J = 6.6 Hz, 1H),7.95 (s, 1H), 7.81 (s, 1H), 7.42 (d, J = 9.9 Hz, 1H), 7.02 (dd, J = 7.1,1.6 Hz, 1H), 6.66 (s, 2H), 2.49-2.43 (m, 1H), 2.24 (d, J = 2.7 Hz, 3H),0.95 (t, J = 3.8 Hz, 2H), 0.92-0.82 (m, 2H) S 154

¹H NMR (400 MHz, DMSO-d₆) δ 8.59 (d, J = 6.6 Hz, 1H), 7.85 (s, 1H), 7.35(q, J = 7.1 Hz, 1H), 7.31-7.15 (m, 2H), 6.97 (dd, J = 7.1, 1.6 Hz, 1H),6.64 (s, 2H), 2.63-2.52 (m, 1H), 2.21 (d, J = 2.2 Hz, 3H), 1.03-0.94 (m,2H), 0.93-0.82 (m, 2H) S 155

¹H NMR (400 MHz, DMSO-d₆) δ 9.50 (s, 1H), 7.48 (dd, J = 9.1, 1.9 Hz,1H), 7.39 (d, J = 8.2 Hz, 1H), 6.66 (s, 2H), 6.42- 6.30 (m, 2H), 5.33(s, 2H), 5.28-5.01 (m, 1H), 2.66-2.52 (m, 1)h, 1.96 (d, J = 2.2 Hz, 3H),1.91-1.75 (m, 1H), 1.14- 1.00 (m, 1H); LCMS (electrospray) m/z 343.10(M + H)+ B 156

¹H NMR (400 MHz, DMSO- d₆) δ 11.21 (s, 1H), 9.85 (s, 1H), 7.86 (dd, J =9.1, 1.9 Hz, 1H), 7.81 (d, J = 1.6 Hz, 1H), 7.51 (d, J = 8.8 Hz, 1H),7.44-7.40 (m, 2H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H), 6.60 (s, 2H), 6.51(t, J = 1.9 Hz, 1H), 5.28- 5.08 (m, 1H), 2.67-2.57 (m, 1H), 1.92- 1.83(m, 1H), 1.14-1.09 (m, 1H); LCMS (electrospray) m/z 335.2 (M + H)+. L157

¹H NMR (400 MHz, DMSO- d₆) δ 11.21 (s, 1H), 9.82 (s, 1H), 7.86 (dd, J =9.1, 1.9 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H),7.44-7.40 (m, 2H), 7.37 (dd, J = 8.5, 1.9 Hz, 1H), 6.61 (s, 2H), 6.50(t, J = 1.9 Hz, 1H), 5.12- 4.94 (m, 1H), 3.12-3.05 (m, 1H), 1.65- 1.57(m, 1H), 1.40-1.36 (m, 1H); LCMS (electrospray) m/z 335.1 (M + H)+. L158

¹H NMR (400 MHz, DMSO- d₆) δ 11.21 (s, 1H), 9.78 (s, 1H), 7.86 (dd, J =9.1, 1.9 Hz, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H),7.44-7.39 (m, 2H), 7.34 (dd, J = 8.5, 1.9 Hz, 1H), 6.60 (s, 2H), 6.50(s, 1h), 5.11-4.94 (m, 1H), 3.11-3.03 (m, 1H), 1.64-1.57 (m, 1H),1.40-1.36 (m, 1H); LCMS (electrospray) m/z 335.1 (M + H)+. L 159

¹H NMR (400 MHz, DMSO-d₆) δ 11.18 (s, 1H), 9.50 (s, 1H), 7.53 (dd, J =9.1, 1.9 Hz, 1H), 7.41-7.38 (m, 2H), 7.31 (d, J = 8.2 Hz, 1H), 7.01 (d,J = 8.2 Hz, 1H), 6.60 (s, 2H), 6.52 (s, 1H), 5.26- 5.07 (m, 1H),2.61-2.56 (m, 1H), 2.42 (s, 3H), 1.87-1.80 (m, 1H), 1.11-1.06 (m, 1H);LCMS (electrospray) m/z 349.2 (M + H)+. L 160

¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (s, 1H), 7.41 (d, J = 1.6 Hz, 2H), 7.21(dd, J = 15.0, 8.2 Hz, 1H), 7.00 (t, J = 8.8 Hz, 1H), 6.74 (d, J = 8.4Hz, 1H), 6.57 (s, 2H), 5.23-5.03 (m, 1H), 2.58- 2.56 (m, 1H), 2.19 (s,3H), 1.85-1.77 (m, 1H), 1.12-1.06 (m, 1H); LCMS (electrospray) m/z 343.9(M + H)+. Q 161

¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 1H), 9.44 (s, 1H), 7.54 (dd, J =9.1, 1.9 Hz, 1H), 7.41-7.37 (m, 2H), 7.30 (d, J = 8.2 Hz, 1H), 6.99 (d,J = 8.2 Hz, 1H), 6.60 (s,2H), 6.52 (s, 1H), 5.08- 4.91 (m, 1H),3.09-3.00 (m, 1H), 2.40 (s, 3H), 1.63-1.55 (m, 1H), 1.37-1.32 (m, 1H);LCMS (electrospray) m/z 349.2 (M + H)+. L 162

¹H NMR (400 MHz, DMSO-d₆) δ 11.17 (s, 1H), 9.45 (s, 1H), 7.54 (dd, J =9.1, 1.9 Hz, 1H), 7.41-7.31 (m, 2H), 7.30 (d, J = 8.2 Hz, 1H), 6.99 (d,J = 8.2 Hz, 1H), 6.60 (s,2H), 6.52 (s, 1H), 5.07- 4.91 (m, 1H),3.09-3.00 (m, 1H), 2.40 (s, 3H), 1.64-1.56 (m, 1H), 1.37-1.32 (m, 1H);LCMS (electrospray) m/z 349.2 (M + H)+. L

Evaluation of Compounds

RIP2 Kinase Assay

GST-tagged recombinant human RIP2 (25 ng) is incubated with 5 μL ofcompounds (0.5% DMSO), 5 μL of MBP (0.5 μg/μl) and 5 μL of ATP (25 μM)in buffer (40 mM Tris, 7.5; 20 mM MgCl₂; 0.1 mg/ml BSA; 50 μM DTT). Theassay was started by incubating the reaction mixture in a 96-well plateat 30° C. for 60 minutes. After the incubation, 25 μL ADP-Glo reagentwas added, and the reaction was incubated at 30° C. for 40 minutes tostop the reaction and degrade residual ATP. The ADP product was thenconverted to ATP by adding 50 μL per well of detection reagent.Luminescence was detected after 30 minutes room temperature incubationwith the Molecular device I3X plate reader. The IC₅₀ values werecalculated from a series of percent inhibition values determined at arange of inhibitor concentration using software routines as implementedin the GraphPad Prism 7 software and SigmaPlot 13.0.

c-Abl Kinase Assay

ADP-Glo assay kit was purchased from Promega. Magnesium chloride(MgCl₂), bovine serum albumin (BSA), ethylene glycol-bis(β-aminoethylether)-N,N,N′,N′-tetraacetic acid (EGTA), tween-20, 1,4-dithiothreitol(DTT) and dimethyl sulfoxide (DMSO) were purchased from Sigma-Aldrich.HEPES buffer was purchased from Gibco. ABL1 kinase and Abltide werepurchased from Signalchem.

c-Abl kinase activity was measured by Promega's ADP-Glo™ Assay. In thisassay, His-tagged recombinant human ABL1 (0.25 ng/μl) is incubated with5 μL of compounds (0.5% DMSO), 5 μL of Abltide (0.01 μg/μl) and 5 μL ofATP (25 μM) in buffer (50 mM HEPES, 7.5; 10 mM MgCl₂; 1 mM EGTA; 0.05%BSA; 0.01% Tween-20; 2 mM DTT). The assay was started by incubating thereaction mixture in a 96-well plate at 30° C. for 30 min. After theincubation, 25 μL ADP-Glo reagent was added and the reaction wasincubated at room temperature for 40-min to stop the reaction anddegrade residual ATP. The ADP product was then converted to ATP byadding 50 μL per well of detection reagent. Luminescence was detectedafter 30-min room temperature incubation with the Molecular device I3Xplate reader. The IC₅₀ values were calculated from a series of percentinhibition values determined at a range of inhibitor concentration usingsoftware routines as implemented in the GraphPad Prism 7 software andSigma Plot 13.0.

IL-6 Secretion in BV-2 Cell

BV-2 mouse microglia cells were kindly provided from Dr. Bae in KoreaInstitute of Science and Technology (KIST). BV-2 cells were thawed andsuspended in Dulbecco's modified eagle medium (DMEM) supplemented with10% fetal bovine serum (FBS) and 1% Penicillin/Streptomycin. Cells wereseeded into 96 well plates at 2×104 cells/well and allowed to attach for24 hr. On the day of the experiment, various concentration of FBcompounds was treated, and cells were stimulated with 10 μg/ml L18-MDP.After 24 hr incubation, supernatant was collected for cytokine assay.

Cytokine secretion was measured after 24 hr post stimulation using IL-6ELISA kit (R&D system) as suggested by the manufacturer. Absorbance at450 nm was measured using SpectraMax i3X microplate reader (MolecularDevice). Values of media-only wells were subtracted and % inhibition foreach compound concentration relative to the DMSO/L18-MDP-treatedcontrols (100%) was calculated. The IC₅₀ values were calculated from aseries of percent activity values using software as implemented in theGraphPad Prism 7 software and SigmaPlot 13.0.

Table 2 shows IC₅₀ values of the invented compounds which represent +for >1000 nM, ++ for 501-1000 nM, +++ for 101-500 nM, ++++ for 1-100 nM.

TABLE 2 In vitro kinase activity and IL-6 secretion in BV-2 cell. RIP2c-Abl IL-6 Example IC₅₀ (nM) IC₅₀ (nM) IC₅₀ (nM) 1 + − − 2 +++ − − 3++++ − + 4 + − − 5 ++++ ++++ ++ 6 +++ − − 7 +++ − − 8 +++ − − 9 +++ − −10 + − − 11 ++++ − − 12 ++++ − − 13 +++ − − 14 ++++ − − 15 ++++ − − 16+++ − − 17 +++ − − 18 +++ − − 19 +++ − − 20 +++ − − 21 +++ − − 22 +++ −− 23 ++ − − 24 + − − 25 +++ − − 26 +++ − − 27 + − − 28 +++ − − 29 +++ −− 30 + − − 31 +++ − − 32 ++++ − +++ 33 + − − 34 +++ − − 35 +++ − − 36 +− − 37 + − − 38 + − − 39 + − − 40 ++++ ++++ +++ 41 ++++ − +++ 42 +++ − −43 +++ − − 44 ++++ − ++ 45 +++ − − 46 ++ − − 47 +++ − − 48 +++ − − 49 +− − 50 ++++ − − 51 ++++ ++++ +++ 52 ++ − − 53 +++ − − 54 + − − 55 + − −56 +++ − − 57 ++++ ++++ +++ 58 ++++ − − 59 ++++ − − 60 ++++ +++ ++++ 61+++ − − 62 +++ − − 63 ++++ − − 64 ++++ − +++ 65 + − + 66 +++ − − 67 ++++− ++ 68 ++++ − +++ 69 ++++ − ++ 70 + − − 71 + − − 72 +++ − − 73 ++++ −+++ 74 ++++ − +++ 75 ++++ − ++ 76 ++++ − − 77 +++ − _ 78 ++++ − − 79++++ − + 80 ++++ − − 81 ++++ − − 82 ++++ − + 83 ++++ − + 84 ++++ − ++ 85++++ − ++ 86 ++++ − + 87 + − − 88 +++ − − 89 ++++ ++++ +++ 90 ++++ − ++91 +++ − − 92 +++ − − 93 + − − 94 ++++ − + 95 ++++ − + 96 +++ − − 97++++ − − 98 + − − 99 +++ − _ 100 ++++ − +++ 101 ++++ − ++ 102 ++++ − −103 +++ − − 104 ++++ ++++ +++ 105 ++++ ++++ +++ 106 +++ − − 107 + − −108 +++ − − 109 +++ − − 110 ++++ − ++ 111 +++ − − 112 + − − 113 ++++++++ +++ 114 ++++ ++++ +++ 115 ++++ − +++ 116 +++ − − 117 ++++ − − 118++++ − − 119 +++ − − 120 +++ − − 121 + − − 122 + − − 123 +++ − − 124 + −− 125 + − − 126 + − − 127 + − − 128 +++ − − 129 +++ − − 130 +++ − − 131+++ − − 132 +++ − − 133 ++++ − − 134 ++++ − − 135 +++ − − 136 + − −137 + − − 138 + − − 139 + − − 140 + − − 141 +++ − − 142 ++++ − − 143 + −− 144 +++ − − 145 ++++ − − 146 +++ − − 147 +++ − − 148 +++ − − 149 + − −150 +++ − − 151 + − − 152 ++++ − +++ 153 ++++ − ++ 154 ++++ − + 155 ++++− − 156 ++++ − − 157 ++++ − − 158 ++++ − − 159 ++++ − − 160 +++ − − 161++++ − − 162 ++++ − − −; not tested

The invention claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areindependently —H, C₁-C₆ alkyl, C₃-C₆ carbocyclyl, C₁-C₄ alkanoyl, —(CO)C₃-C₆ carbocyclyl, aryl, or heteroaryl, wherein each R¹ and R² isoptionally substituted with one or more groups selected from the groupconsisting of halo, alkyl, hydroxyalkyl, haloalkyl, andmonoalkylaminoalkyl; or R¹ and R² together form a 5-member heterocycle;R³ is —H, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl,—O-cycloalkyl, —O— heterocyclyl, —O-aryl, —O-heteroaryl, —NR_(c)-alkyl,—NR_(c)-cycloalkyl, —NR_(c)-heterocyclyl, —NR_(c)-aryl,—NR_(c)-heteroaryl, —NR_(c)—NR_(c) C(═O)R_(c) or —CF₃, wherein R³ isoptionally substituted with one or more groups selected from the groupconsisting of halo, alkyl, hydroxyalkyl, haloalkyl, andmonoalkylaminoalkyl; R⁴ and R⁵ are independently —H, —OH, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, aryl, heteroaryl, heterocyclyl, heteroalkyl, amino,—SCH₃, or —CN; R⁶ is selected from the group consisting of —H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ carbocyclyl, heterocyclyl, aryl,heteroaryl, —NR_(c)-aryl, —NR_(c)-heteroaryl, —O-aryl, —O— heteroaryl,wherein R⁶ is optionally substituted with one or more groups selectedfrom the group consisting of halo, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, hydroxyalkyl, aminoalkyl, trimethylsilylethoxymethyl,morpholinyl, piperazinyl, methylpiperazinyl, alkoxyalkenyl, —NO₂,—NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)C(═O)NR_(a)R_(b),—NR_(a)C(═O)OR_(b), —OR_(a), —SR_(a), —CN, —C(═O)R_(a), —C(═O)OR_(a),—C(═O)NR_(a)R_(b), —OC(═O)R_(a), —OC(═O)OR_(a), and —OC(═O)NR_(a)R_(b);R_(a) and R_(b) are independently —H, halo, amino, alkyl, or haloalkyl;R_(c) is —H, C₁-C₃ alkyl, or cyclopropyl; X is N; and Y is C, whereinR⁴, R⁵, and R⁶ are not each —H.
 2. The compound of claim 1, wherein R³is selected from the group consisting of —H, methyl, isopropyl, butyl,methoxy, pyridinyl, phenyl, cyclopropyl, cyclobutyl, pyrazolyl,azetidinyl, pyrimidinyl, pyrrolidinyl, cyclopropylamino, and indazolyl,wherein R³ is optionally substituted with one or more groups selectedfrom the group consisting of halo, alkyl, hydroxyalkyl, haloalkyl, andmonoalkylaminoalkyl.
 3. The compound of claim 1, wherein R⁶ is selectedfrom the group consisting of bromo, phenyl, pyridinyl, pyrimidinyl,pyridazinyl, pyrazinyl, aza-indolinyl, indolyl, pyrrolyl, pyrazolyl,imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl, oxazolyl,thiazolyl, oxadiazolyl, thiadiazolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazolopyridinyl,imidazolopyridinyl, imidazolopyrimidinyl, imidazopyrazinyl,pyrrolotriazinyl, pyrazolopyridinyl, imidazolotriazinyl, purinyl,indazolyl, benzofuranyl, benzothiophenyl, benzooxazolinyl,benzothiazolinyl, benzoimidazolyl, oxoindolinyl, quinolinyl,aza-quinolinyl, isoquinolinyl, aza-isoquinolinyl, quinazolinyl,aza-quinazolinyl, quinoxalinyl, aza-quinoxalinyl, naphthalenyl, whereinR⁶ is optionally substituted with one or more groups selected from thegroup consisting of halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,haloalkoxy, hydroxyalkyl, aminoalkyl, alkylamino,trimethylsilylethoxymethyl, morpholinyl, piperazinyl, methylpiperazinyl,and alkoxyalkenyl.
 4. The compound of claim 1, which is selected fromcompounds of Formula (II) and pharmaceutically acceptable salts thereof:

wherein R³ is —H, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl,heteroaryl, —O-cycloalkyl, —O— heterocyclyl, —O-aryl, —O-heteroaryl,—NR_(c)-alkyl, —NR_(c)-cycloalkyl, —NR_(c)-heterocyclyl, —NR_(c)-aryl,—NR_(c)-heteroaryl, —NR_(c)—NR_(c) C(═O)R_(c) or —CF₃, wherein R³ isoptionally substituted with one or more groups selected from the groupconsisting of halo, alkyl, hydroxyalkyl, haloalkyl, andmonoalkylaminoalkyl; R⁴ and R⁵ are independently —H, —OH, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, aryl, heteroaryl, heterocyclyl, heteroalkyl, amino,—SCH₃, or —CN; R⁶ is selected from the group consisting of —H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ carbocyclyl, heterocyclyl, aryl,heteroaryl, —NR_(c)-aryl, —NR_(c)-heteroaryl, —O-aryl, —O— heteroaryl,wherein R⁶ is optionally substituted with one or more groups selectedfrom the group consisting of halo, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, hydroxyalkyl, aminoalkyl, trimethylsilylethoxymethyl,morpholinyl, piperazinyl, methylpiperazinyl, alkoxyalkenyl, —NO₂,—NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)C(═O)NR_(a)R_(b),—NR_(a)C(═O)OR_(b), —OR_(a), —SR_(a), —CN, —C(═O)R_(a), —C(═O)OR_(a),—C(═O)NR_(a)R_(b), —OC(═O)R_(a), —OC(═O)OR_(a), and —OC(═O)NR_(a)R_(b);R_(a) and R_(b) are independently —H, halo, amino, alkyl, or haloalkyl;and R_(c) is —H, C₁-C₃ alkyl, or cyclopropyl.
 5. The compound of claim4, wherein R³ is fluorocyclopropyl and R⁶ is indolyl which is optionallysubstituted with one or more groups selected from the group consistingof halo, hydroxyl, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, andtert-butoxycarbonyl.
 6. The compound of claim 5, which is selected fromthe group consisting of:(2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-indol-6-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-indol-7-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-8-fluoro-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-chloro-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-8-fluoro-6-(1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-methyl-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-fluoro-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-chloro-1H-indol-3-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(6-fluoro-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(6-fluoro-5-methyl-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1R,2R)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2R)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1R,2R)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2R)-2-fluorocyclopropyl)methanone;tert-butyl3-(2-amino-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)-1H-indole-1-carboxylate;and(2-amino-6-(1H-indol-3-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone.7. The compound of claim 5, which is selected from the group consistingof:(2-amino-6-(4-methyl-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-chloro-1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(6-fluoro-5-methyl-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-methyl-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-fluoro-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(6-fluoro-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;and(2-amino-6-(6-fluoro-5-methyl-1H-indol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone.8. The compound of claim 4, wherein R³ is fluorocyclopropyl, and R⁶ isselected from the group consisting of bromo, phenyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, aza-indolinyl, indolyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl,oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazolopyridinyl,imidazolopyridinyl, imidazolopyrimidinyl, imidazopyrazinyl,pyrrolotriazinyl, pyrazolopyridinyl, imidazolotriazinyl, purinyl,indazolyl, benzofuranyl, benzothiophenyl, benzooxazolinyl,benzothiazolinyl, benzoimidazolyl, oxoindolinyl, quinolinyl,aza-quinolinyl, isoquinolinyl, aza-isoquinolinyl, quinazolinyl,aza-quinazolinyl, quinoxalinyl, aza-quinoxalinyl, naphthalenyl, whereinR⁶ is optionally substituted with one or more groups selected from thegroup consisting of halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,haloalkoxy, hydroxyalkyl, aminoakyl, alkylamino,trimethylsilylethoxymethyl, morpholinyl, piperazyinyl,methylpieprazinyl, and alkoxyalkenyl.
 9. The compound of claim 8, whichis selected from the group consisting of:(2-amino-6-bromoimidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(thiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2,3-dimethylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2,5-dimethylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2,4-dimethylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-fluoro-6-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-methyl-3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-fluoro-6-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(furan-2-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-methylthiazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-methylthiophen-2-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(thiazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3,4-difluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-chlorophenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2R)-2-fluorocyclopropyl)methanone;1-(4-(2-amino-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)-3-methylphenyl)ethan-1-one;(2-amino-6-(4-morpholinophenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2R)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-chloro-3-fluorophenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-methyl-5-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(S)-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(2,2-difluorocyclopropyl)methanone;(2-amino-6-(4-(piperazin-1-yl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-(4-methylpiperazin-1-yl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-(4-methylpiperazin-1-yl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(7-(dimethylamino)-6-fluoro-5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(6-fluoro-5-methyl-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(benzofuran-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-chloro-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-fluoro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-methylisothiazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-chloro-1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-methyl-1H-indazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-8-fluoro-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-8-fluoro-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-benzo[d]imidazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-methyl-1H-benzo[d]imidazol-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-pyrrolo[2,3-b]pyridin-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1,4-dimethyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;2-amino-6-(3-fluoro-2-methylphenyl)-N-((1R,2S)-2-fluorocyclopropyl)imidazo[1,2-a]pyridine-3-carboxamide;(2-amino-6-(1H-pyrrolo[2,3-b]pyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(quinolin-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(quinolin-3-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(isoquinolin-4-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(o-tolyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-(2-fluoroethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-(2-fluoroethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;tert-butyl2-(2-amino-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)-1H-pyrrole-1-carboxylate;tert-butyl3-(2-amino-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)-1H-pyrrole-1-carboxylate;(2-amino-6-(3-fluoro-2-(3-hydroxypropyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-pyrrol-2-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(1H-pyrrol-3-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-(2-hydroxyethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-(hydroxymethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-(2-hydroxyethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-(3-hydroxypropyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-(2-fluoroethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-(3-fluoropropyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-(3-fluoropropyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-amino-5-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(4-amino-2-fluoro-5-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-(2-fluoroethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;tert-butyl(2-(2-amino-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-6-yl)benzyl)carbamate;(2-amino-6-(2-(aminomethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-(2-fluoroethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2R)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-(2-fluoroethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-(2-fluoroethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2R)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-amino-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(2-amino-6-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-((E)-2-methoxyvinyl)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-vinylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-fluoro-2-methyl-3-(methylamino)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-(dimethylamino)-5-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-((3-fluoro-2-methylphenyl)amino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-amino-6-(3-fluoro-2-(2-fluoroethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2R)-2-fluorocyclopropyl)methanone;(2-amino-6-(5-amino-3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;and (2-amino-6-(3-fluoro-2-methylphenoxy)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone.10. The compound of claim 4, wherein R³ is cyclopropyl and R⁶ isselected from the group consisting of bromo, phenyl, pyridinyl,pyrimidinyl, pyridazinyl, pyrazinyl, aza-indolinyl, indolyl, pyrrolyl,pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thiophenyl, furanyl,oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, pyrrolopyridinyl,pyrrolopyrimidinyl, pyrazolopyrimidinyl, imidazolopyridinyl,imidazolopyridinyl, imidazolopyrimidinyl, imidazopyrazinyl,pyrrolotriazinyl, pyrazolopyridinyl, imidazolotriazinyl, purinyl,indazolyl, benzofuranyl, benzothiophenyl, benzooxazolinyl,benzothiazolinyl, benzoimidazolyl, oxoindolinyl, quinolinyl,aza-quinolinyl, isoquinolinyl, aza-isoquinolinyl, quinazolinyl,aza-quinazolinyl, quinoxalinyl, aza-quinoxalinyl, naphthalenyl, whereinR⁶ is optionally substituted with one or more groups selected from thegroup consisting of halo, hydroxyl, alkyl, alkenyl, alkynyl, haloalkyl,haloalkoxy, hydroxyalkyl, aminoalkyl, alkylamino,trimethylsilylethoxymethyl, morpholinyl, piperazinyl, methylpiperazinyl,and alkoxyalkenyl.
 11. The compound of claim 10, which is selected fromthe group consisting of:(2-amino-6-bromoimidazo[1,2-a]pyridin-3-yl)(cyclopropyl)methanone;(2-amino-6-(4-methylpyridin-3-yl)imidazo[1,2-a]pyridin-3-yl)(cyclopropyl)methanone;(2-amino-6-(5-methyl-1H-indazol-4-yl)imidazo[1,2-a]pyridin-3-yl)(cyclopropyl)methanone;and(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(cyclopropyl)methanone.12. The compound of claim 4, wherein R³ is selected from the groupconsisting of methyl, isopropyl, butyl, methoxy, pyridinyl, phenyl,cyclobutyl, pyrazolyl, azetidinyl, pyrimidinyl, pyrrolidinyl,cyclopropylamino, and indazolyl, wherein R³ is optionally substitutedwith one or more groups selected from the group consisting of halo,alkyl, hydroxyalkyl, haloalkyl, and monoalkylaminoalkyl.
 13. Thecompound of claim 12, which is selected from the group consisting of:1-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)ethan-1-one;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)methanone;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(phenyl)methanone;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(cyclobutyl)methanone;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(1-methyl-1H-pyrazol-4-yl)methanone;1-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)-2,2-dimethylpropan-1-one;1-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)pentan-1-one;tert-butyl2-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carbonyl)azetidine-1-carboxylate;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(3,3-difluorocyclobutyl)methanone;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(azetidin-2-yl)methanone;tert-butyl3-(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carbonyl)azetidine-1-carboxylate;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(azetidin-3-yl)methanone;(2-amino-6-(1H-indol-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)methanone;(2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)methanone;(2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)methanone;(2-amino-6-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyridin-2-yl)methanone;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-2-yl)methanone;(2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-4-yl)methanone;(2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-4-yl)methanone;(2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-2-yl)methanone;(2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(azetidin-3-yl)methanone;(2-amino-6-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(azetidin-3-yl)methanone;(2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-4-yl)methanone;(2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrimidin-2-yl)methanone;(2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(azetidin-3-yl)methanone;(2-amino-6-(1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrrolidin-3-yl)methanone;(2-amino-6-(4-methyl-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrrolidin-3-yl)methanone;(2-amino-6-(4-chloro-1H-pyrrolo[2,3-b]pyridin-5-yl)imidazo[1,2-a]pyridin-3-yl)(pyrrolidin-3-yl)methanone;2-amino-N-cyclopropyl-6-(3-fluoro-2-methylphenyl)-N-methylimidazo[1,2-a]pyridine-3-carboxamide;2-amino-N-cyclopropyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxamide;N′-acetyl-2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carbohydrazide;methyl2-amino-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridine-3-carboxylate;2-amino-6-(5-chloro-7-(dimethylamino)-6-fluoro-1H-indazol-4-yl)-N-cyclopropylimidazo[1,2-a]pyridine-3-carboxamide;and (3S,4R)-4-methyltetrahydrofuran-3-yl2-amino-6-(5-chloro-6-fluoro-7-(methylthio)-1H-indazol-4-yl)imidazo[1,2-a]pyridine-3-carboxylate.14. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: R¹ and R² areindependently —H, C₁-C₆ alkyl, C₃-C₆ carbocyclyl, C₁-C₄ alkanoyl, —(CO)C₃-C₆ carbocyclyl, aryl, or heteroaryl, wherein each R¹ and R² isoptionally substituted with one or more groups selected from the groupconsisting of halo, alkyl, hydroxyalkyl, haloalkyl, andmonoalkylaminoalkyl; or R¹ and R² together form a 5-member heterocycle;R³ is —H, alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl,—O-cycloalkyl, —O— heterocyclyl, —O-aryl, —O-heteroaryl, —NR_(c)-alkyl,—NR_(c)-cycloalkyl, —NR_(c)-heterocyclyl, —NR_(c)-aryl,—NR_(c)-heteroaryl, —NR_(c)—NR_(c) C(═O)R_(c) or —CF₃, wherein R³ isoptionally substituted with one or more groups selected from the groupconsisting of halo, alkyl, hydroxyalkyl, haloalkyl, andmonoalkylaminoalkyl; R⁴ and R⁵ are independently —H, —OH, halo, C₁-C₆alkyl, C₁-C₆ alkoxy, aryl, heteroaryl, heterocyclyl, heteroalkyl, amino,—SCH₃, or —CN; R⁶ is selected from the group consisting of —H, halo,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₃-C₆ carbocyclyl, heterocyclyl, aryl,heteroaryl, —NR_(c)-aryl, —NR_(c)-heteroaryl, —O-aryl, —O-heteroaryl,wherein R⁶ is optionally substituted with one or more groups selectedfrom the group consisting of halo, hydroxyl, alkyl, alkenyl, alkynyl,haloalkyl, hydroxyalkyl, aminoalkyl, trimethylsilylethoxymethyl,morpholinyl, piperazinyl, methylpiperazinyl, alkoxyalkenyl, —NO₂,—NR_(a)R_(b), —NR_(a)C(═O)R_(b), —NR_(a)C(═O)NR_(a)R_(b),—NR_(a)C(═O)OR_(b), —OR_(a), —SR_(a), —CN, —C(═O)R_(a), —C(═O)OR_(a),—C(═O)NR_(a)R_(b), —OC(═O)R_(a), —OC(═O)OR_(a), and —OC(═O)NR_(a)R_(b);R_(a) and R_(b) are independently —H, halo, amino, alkyl, or haloalkyl;R_(c) is —H, C₁-C₃ alkyl, or cyclopropyl; X is C; and Y is N, whereinR⁴, R⁵, and R⁶ are not each —H.
 15. The compound of claim 14, which is(2-amino-5-(1H-indol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)(cyclopropyl)methanone;(2-amino-5-(6-fluoro-5-methyl-1H-indazol-4-yl)pyrazolo[1,5-a]pyridin-3-yl)(cyclopropyl)methanone;and(2-amino-5-(3-fluoro-2-methylphenyl)pyrazolo[1,5-a]pyridin-3-yl)(cyclopropyl)methanone.16. The compound of claim 1, wherein R¹ and R² are independently —H,alkyl, acetyl, tert-butoxycarbonyl, aminoethyl, dimethylaminoethyl, ormethylaminoethyl; or R¹ and R² together form a 5-member heterocycle. 17.The compound of claim 16, which is selected from the group consistingof:(2-((2-(dimethylamino)ethyl)amino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-((2-aminoethyl)amino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;N-acetyl-N-(3-acetyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamide;(6-(3-fluoro-2-methylphenyl)-2-(methylamino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(2-(dimethylamino)-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-3-yl)((1R,2S)-2-fluorocyclopropyl)methanone;tert-butyl(6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)carbamate;(6-(3-fluoro-2-methylphenyl)-2-(pyrrolidin-1-yl)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;(6-(3-fluoro-2-methylphenyl)-2-((2-(methylamino)ethyl)amino)imidazo[1,2-a]pyridin-3-yl)((1S,2S)-2-fluorocyclopropyl)methanone;N-(6-(3-fluoro-2-methylphenyl)-3-((1S,2S)-2-fluorocyclopropane-1-carbonyl)imidazo[1,2-a]pyridin-2-yl)acetamido;andN-(3-acetyl-6-(3-fluoro-2-methylphenyl)imidazo[1,2-a]pyridin-2-yl)acetamido.18. The compound of claim 1, wherein the salt is hydrochloric acid salt,tartaric acid salt, phosphoric acid salt, or maleic acid salt.
 19. Apharmaceutical composition comprising a therapeutically effective amountof the compound of claim 1 or a pharmaceutically acceptable saltthereof, and at least one pharmaceutically acceptable carrier.
 20. Thepharmaceutical composition of claim 19, further comprising one or moreactive ingredient that is useful to treat a neurodegenerative disease.21. A method for treating an inflammatory and autoimmune disease in asubject, comprising: administering to the subject in need thereof atherapeutically effective amount of the compound of claim 1 or apharmaceutically acceptable salt thereof, wherein the inflammatory andautoimmune disease is selected from the group consisting ofα-synucleinopathy, Parkinson's disease, dementia with Lewy body,multiple system atrophy (MSA), Alzheimer's disease, and amyotrophiclateral sclerosis (ALS).
 22. The method of claim 21, wherein the subjectis a human.